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Interpretations
This list does not include generic interpretations. You can see a list of generic interpretations here.

Interpretations

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Tier 1
CSF3R
Variants
CSF3R T618I
CSF3R any nonsense
CSF3R any frameshift
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Chronic Neutrophilic Leukemia
Atypical Chronic Myeloid Leukemia
Interpretation

The activating missense membrane-proximal mutation in CSF3R (p.T618I) has been reported to occur in approximately 83% of cases of chronic neutrophilic leukemia; some reports indicate this mutation may be present in cases of atypical chronic myeloid leukemia as well. The CS3R T618I mutation has been associated with response to JAK2 inhibitors but not dasatinib. A germline activating CSF3R mutation (p. T617N) has been described in autosomal dominant hereditary neutrophilia associated with splenomegaly and increased circulating CD34-positive myeloid progenitors. Nonsense and/or frameshift somatic mutations truncating the cytoplasmic domain of CSF3R have been described in approximately 40% of patients with severe congenital neutropenia and in the context of mutations in other genes may be associated with progression to acute myeloid leukemia. These activating truncating mutations have also been found in patients with chronic neutrophilic leukemia or atypical chronic myeloid leukemia. Some of these cytoplasmic truncating mutations have been associated with responses to dasatinib but not JAK2 inhibitors.

Last updated: 2020-07-24 14:50:32 UTC
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Tier 1
MPL
Variants
MPL codon(s) 515 missense
MPL W515L
MPL W515K
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Essential Thrombocythemia
Primary Myelofibrosis
Acute Leukemia of Unspecified Cell Type
Acute Myeloid Leukemia
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

MPL encodes the thrombopoietin receptor, an important growth and survival factor for megakaryocytes. Somatic activating mutation in MPL (W515L, W515K) has been reported in approximately 1%-10% of cases of JAK2 V617F-negative myelofibrosis, essential thrombocythemia, a subset of cases of acute megakaryoblastic leukemia and has been associated with sensitivity to JAK inhibitors. The W515 mutations are typically not observed in polycythemia vera or other myeloid disorders (chronic myelomonocytic leukemia, myelodysplastic syndrome). A S505N activating mutation has also been described in familial essential thrombocythemia. MPL mutation is included as one of the major diagnostic criteria for primary myelofibrosis and essential thrombocythemia in the 2016 revision of the WHO classification.

Last updated: 2018-11-12 20:40:42 UTC
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Tier 2
JAK1
Variants
JAK1 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
T Lymphoblastic Leukemia/Lymphoma
Acute Myeloid Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

Activating mutations in JAK1 (SH2-, pseudokinase -and kinase- domains) have been reported in approximately 5-20% of cases of T-Cell Acute Lymphoblastic Leukemia, in "Ph-like ALL" and in less than 5% of Acute Myeloid Leukemia. Some, but not all, of these mutations have been shown to be inhibitable by ATP-competitive JAK inhibitors or Type I interferon.

Last updated: 2019-08-28 14:54:00 UTC
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Tier 1
NRAS
Variants
NRAS any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Myelodysplastic Syndrome
B Lymphoblastic Leukemia/Lymphoma
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

NRAS encodes a membrane protein GTPase that is a central mediator of downstream growth factor receptor signaling, critical for cell proliferation and survival. Mutations in codons 12, 13, and 61 of NRAS have been reported in 7-22% of acute myeloid leukemia, 12% of chronic myelomonocytic leukemia, 20% of blastic plasmacytoid dendritic cell neoplasm, 16% of juvenile myelomonocytic leukemia, 4-10% of myelodysplastic syndromes, and 5% of primary myelofibrosis. In addition, NRAS mutations have been described in approximately 15% of cases of B-ALL and, interestingly, some cases of ALL may show more than one abnormality in the RAS pathway. NRAS mutations are associated with an unfavorable prognosis in chronic myelomonocytic leukemia and primary myelofibrosis. NRAS mutations are also associated with an unfavorable prognosis in myelodysplastic syndrome, particularly in patients predicted to have lower-risk myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic Syndromes). NRAS mutations do not seem to have significant prognostic impact in AML.

Last updated: 2019-08-28 14:54:00 UTC
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Tier 1
NOTCH2
Variants
NOTCH2 I2304fs
NOTCH2 exon(s) 34 frameshift
Primary Sites
Blood
Bone Marrow
Tumor Types
Marginal Zone B Cell Lymphoma
Diffuse Large B Cell Lymphoma
Interpretation

NOTCH2 gain of function mutations have been reported in apprximately 25% of splenic marginal zone lymphomas and are thought to be rare in non-splenic marginal zone lymphomas. These mutations are typically located near the C-terminal PEST domain and lead to protein truncation or, more rarely, are nonsynonymous substitution mutations affected the extracellular heterodimerization domain. NOTCH2 mutations may be associated with a worse prognosis among cases of splenic marginal zone lymphoma. In addition, NOTCH2 PEST domain mutations have been reported in approximately 8% of diffuse large B cell lymphomas and in vitro systems have demonstrated these PEST domain mutant NOTCH2 receptors have increased activity compared to wild type NOTCH2. In addion, copy number gain has been reported in a subset of DLBCL cases with NOTCH2 mutations.

Last updated: 2016-06-04 21:03:16 UTC
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Tier 1
RIT1
Variants
RIT1 M90I
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Interpretation

Ras-like-without-CAAX-1 (RIT1) gene is a member of the RAS gene family. Recurrent somatic mutations of RIT1 have been reported in approximately 7% of cases of chronic myelomonocytic leukemia, and less than 5% of cases of myelodysplastic syndrome and less than 5% of acute myeloid leukemia. The mutations typically occur in the Switch II effector domain, and the affected residues are close to codon Q79, which is analogous to amino acid Q61 of NRAS or KRAS where mutations frequently occur in cancer. Moreover, the experimental Q79L mutation in RIT1 has been reported to confer constitutive activation of the protein. RIT1 mutations are typically mutually exclusive of mutations in other RAS family members. In addition, RIT1 maps to the minimal common amplified region (1q21-22) in 1q gains frequently found in other cancers. 1q amplification involving the RIT1 locus has been reported in 4-18% of cases of myelofibrosis as well as less than 5% of chronic myelomonocytic leukemia, less than 5% of myelodysplastic syndromes and less than 5% of acute myeloid luekemia. In rare cases mutations and amplifcations of RIT1 may coexist. In general, RIT1 has been reported to increased phosphorylation of AKT and activate proliferation through the mitogen activated protein kinase pathway.

Last updated: 2020-07-24 14:53:26 UTC
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Tier 2
DNMT3A
Variants
DNMT3A any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Acute Myeloid Leukemia
T Lymphoblastic Leukemia/Lymphoma
Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

DNMT3A is a DNA methyltransferase. Recurrent, somatic, heterozygous mutations in DNMT3A have been reported in approximately 18-25% of cases of acute myeloid leukemia (up to 34% of normal karyotype AML), 12-18% of cases of myelodysplastic syndrome, up to 15% of myeloproliferative neoplasms, less than 5% of cases of chronic myelomonocytic leukemia and 15% of cases of adult, eary T cell precursor acute lymphoblastic leukemia. DNMT3A is also one of the most frequently mutated genes in CHIP and CCUS. Mutations in DNMT3A may occur together with mutations in other genes including JAK2, FLT3, IDH1/IDH2, ASXL1, TET2 and NPM1. DNMT3A mutations have been associated with reduced enzymatic activity or altered histone binding, as well as reduced DNA methylation in various genomic regions and altered gene expression in some models. Codon R882 is a hotspot for mutations in DNMT3A. DNMT3A mutations may be associated with adverse prognosis in specific subtypes of AML according to some, but not all studies; the prognostic significance of DNMT3A in AML may depend on patient age, type of DNMT3A mutation (R882 or non-R882 mutation) and the co-existence (or absence) of specific mutations in other genes. DNMT3A mutations may also be associated with adverse prognosis in MDS according to some studies.

Last updated: 2019-08-28 14:54:00 UTC
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Tier 1
FANCL
Variants
FANCL any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Myelodysplastic Syndrome
Interpretation

Fanconi anemia is a rare genetic syndrome characterized by developmental defects, bone marrow failure and increased cancer risk. A diagnosis of Fanconi Anemia usually requires detection of a pathogenic mutation in a Fanconi Anemia gene and/or a positive chromosomal breakage test. A variety of different inactivating mutations in FANCL have been described in a small subset of patients with Fanconi Anemia and patients with myeldodysplastic syndrome(less than 5%). Pathogenic mutations are often found in homozygous or compound heterozygous state. In addition, pathogenic variants in introns have been described that are not detected by this test.

Last updated: 2019-05-23 22:48:15 UTC
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Tier 1
XPO1
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Chronic Lymphocytic Leukemia
Interpretation

The nuclear export protein, XPO1, is mutated in less than 5% of cases of chronic lymphocytic leukemia (CLL). Most frequently these mutations affect codon Glu571. Cases of CLL with mutations in XPO1 tend to be associated with a higher prevalence of CD38 expression (>30% of tumor cells), ZAP70 expression (> 20% of tumor cells), concomitnat NOTCH1 mutation and unmutated IGHV. Given the low prevalence of XPO1 mutations, prognostic signficance has not been firmly establlished. XPO1 has been successfully targeted in some experimental models of CLL.

Last updated: 2016-06-04 21:09:01 UTC
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Tier 1
CXCR4
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Lymphoplasmacytic Lymphoma
Interpretation

CXCR4 is a chemokine receptor which has been shown to mutated in approximately 25-30% of patients with Waldenstrom's Macroglobulinemia(WM). The mutations are nonsense and frameshift mutations in the carboxy terminus of the protein. Similar mutations are found in WHIM (Warts, Hypogammaglobulinemia, Infection and Myelokathexis) syndrome, a rare, autsomal dominant genetic disorder. These mutations in the carboxy terminal tail lead to impaired receptor desensitization and internalization, resulting in enhanced receptor activation and increased expression. Almost all WM patients with mutation of CXCR4 also carry the MYD88 L265P mutation. Mutations in CXCR4 appear to be mutually exclusive of mutations in CD79A/CD79B. Patients with CXCR4 mutations may be candidates for targeted therapy since CXCR4 antagonists have been used in patients with WHIM syndrome. The presence of CXCR4 mutations may affect response to Ibrutinib therapy according to some studies.

Last updated: 2016-02-13 22:39:54 UTC
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Tier 1
SF3B1
Variants
SF3B1 codon(s) 700, 666, 662, 625, 622 missense
SF3B1 exon(s) 13-16 missense
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
MDS with Ring Sideroblasts
Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Acute Myeloid Leukemia
Primary Myelofibrosis
Essential Thrombocythemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

SF3B1 encodes a core component of the U2 small nuclear ribonucleoprotein, involved in the recognition of the branchpoint sequence during RNA splicing. SF3B1 is one of several genes involved in RNA splicing that has been identified as recurrently mutated in MDS and other malignancies. SF3B1 is the most commonly mutated gene found in MDS (20-33% of MDS overall). SF3B1 mutations are highly associated with subtypes of MDS characterized by ring sideroblasts (MDS with ring sideroblasts and MDS with multilineage dysplasia and ring sideroblasts), present in ~80% of these patients. In addition, many cases (60-80%) of myelodysplastic/myeloproliferative neoplasm with ring sideroblast and thrombocytosis (MDS/MPN-RS-T) harbor SF3B1 mutations. SF3B1 mutations are also found in 12% of blastic plasmacytoid dendritic cell neoplasm, 4-7% of primary myelofibrosis, 5% of CMML, less than 5% of de novo AML and less than 5% of essential thrombocythemia and polycythemia vera. SF3B1 mutations tend to occur in exons 13-16 and appear to be enriched at codons Lys700, Lys666, His662, Arg625 and Glu622. Missense mutations have been reported in approximately 5-10% of cases of chronic lymphocytic leukemia (CLL) and are reported to be associated with del11q , unmutated IGHV and may predict an adverse prognosis in CLL. Mutations in splicing factor components are usually mutually exclusive. Among cases of CLL, SF3B1 mutations tend to be exclusive of NOTCH1 mutations according to one study. The presence of SF3B1 mutation has been included in the diagnostic criteria for MDS/MPN-RS-T and MDS-RS diagnosis in the 2016 revision of the WHO classification. SF3B1 mutations are independently associated with a more favorable prognosis in MDS (NCCN Guidelines for Myelodysplastic Syndromes) and are highly predictive for the presence of ring sideroblasts. SF3B1 mutations are also reported to be highly specific for secondary acute myeloid leukemia, and may also be helpful in identifying a subset of therapy-related AML or elderly patients with de novo acute myeloid leukemia with worse clinical outcomes. SF3B1 mutations are associated with an unfavorable prognosis in essential thrombocythemia. SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processes/pathways, many of which are relevant to the known MDS-RS pathophysiology, suggesting a causal link.

Last updated: 2018-11-12 20:40:56 UTC
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Tier 1
IDH1
Variants
IDH1 R132H
IDH1 R132L
IDH1 R132C
IDH1 codon(s) 132 any
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Primary Myelofibrosis
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

IDH1 is an enzyme localized to the cytoplasm and peroxisomes and involved in citrate metabolism. Mutations at Arg132 of IDH1 are typically heterozygous mutations and considered gain of function mutations that lead to increased levels of 2-hydroxyglutarate which are believed to alter epigenetic regulation (ie, DNA methylation) in AML. Mutations of IDH1 appear to be mutually exclusive of mutations in TET2, another gene involved in regulation of DNA methylation, and also exclusive of mutations in IDH2. Mutations of IDH1 have been shown to lead to increased DNA methylation in AML. Recurrent missense mutation of Arg 132 in IDH1 has been reported in approximately 5-15% of cases of acute myeloid leukemia and is often associated with a normal karyotype, wild type CEBPA, wild type FLT3 and the presence of NPM1 mutations. In addition, this mutation has been reported in approximately 10-20% of cases with leukemic transformation of myeloproliferative neoplasms and has been reported in less than 5% of chronic phase primary myelofibrosis, less than 5% of myelodysplastic syndrome and rare cases of polycythemia vera, essential thrombocytosis and chronic myelomonocytic leukemia. The prognostic impact of IDH1 mutations in AML appears uncertain, however, in the settings of primary myelofibrosis and polycythemia vera, the presence of IDH1 mutation is independently associated with inferior survival. Mutant IDH1 represents a therapeutic target in some clinical settings.

Last updated: 2018-11-12 20:41:31 UTC
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Tier 2
IKZF2
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
B Lymphoblastic Leukemia/Lymphoma
T Lymphoblastic Leukemia/Lymphoma
Interpretation

Copy number loss of in IKZF2 (HELIOS) have been described in approximately 50-60% of low haploid acute lymphoblastic leukemia. Occasional inactivating mutations of IKZF2 have also been described. IKZF2 and Ras pathway alterations are usually mutually exclisive according to one report. In some experimental models, higher amounts of pERK and pS6 were observed after knockdown of Ikzf2 in cell lines. This raises the possibility that IKZF2 is a modulator of Ras and PI3K signaling and the efficacy of therapeutic targeting of PI3K and mTOR in such cases remains to be determined.

Last updated: 2016-06-04 21:20:50 UTC
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Tier 1
MYD88
Variants
MYD88 L265P
Primary Sites
Blood
Bone Marrow
Tumor Types
Lymphoplasmacytic Lymphoma
Interpretation

MYD88 is an adaptor protein in the Toll-like receptor and interleukin 1 receptor pathway which mediates activation of NF-KB. The somatic, activating mutation in MYD88 (p.L265P) has been reported in approximately 90% of lymphoplasmacytic lymphoma (Waldenostrom's macroglobuinemia), 20-30% of cases of diffuse large B cell lymphoma (DLBCL), 10-60% of IgM MGUS, 10% of MALT lymphoma and up to 10% of chronic lymphocytic leukemia. It has not been reported in acute leukemia or multiple myeloma (including IgM myeloma). The L265P mutation increases in NFkB activity, JAK-STAT3 (Janus kinase-signal transducer and activator of transcription 3) signalling and interferon-b production. Targetted therapy using inhibitors of the different components of this pathway are at various stages of investigation. Responses to targeted therapy with Ibrutinib may vary according to MYD88 and CXCR4 mutation status according to some studies.

Last updated: 2020-07-24 14:53:37 UTC
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Tier 1
CTNNB1
Variants
CTNNB1 codon(s) 32, 33, 34, 35, 36, 37, 41, 45 any
CTNNB1 S45P
CTNNB1 G34E
CTNNB1 S37C
CTNNB1 S37F
CTNNB1 D32V
CTNNB1 codon(s) 41, 45 any
CTNNB1 S37Y
Primary Sites
Blood
Bone Marrow
Tumor Types
Myelodysplastic Syndrome
Acute Myeloid Leukemia
Interpretation

Beta catenin is a transcriptional co-regulator and an adapter protein for cellular adhesion; it comprises part of the Wnt signaling pathway and intracellular levels of beta-catenin are regulated by its phosphorylation, ubiquitination and proteosomal degradation. Accumulation of nuclear beta catenin can lead to a tumoral phenotype and oncogenic transformation in a variety of solid tumors. Various oncogenic mutants of beta catenin have been found in different tumor types which alter its degradation, leading to its accumulation and promoting tumor growth. Some of these mutations are located at the N-terminus of the protein at the sites of phosphorylation which normally regulate its degradation. Interestingly, in a recent study, 38% of patients with myelodysplastic syndromes or acute myeloid leukaemia, showed increased β-catenin signalling and nuclear accumulation of beta catenin in osteoblasts was associated with increased Notch signalling in haematopoietic cells consistent with a model where abnormalities of osteolineage cells are associated with myeloid malignancies. In addition, aberrant Wnt siganling has been reported to play a role in chronic myeloid leukemia, acute lymphoblastic leukemia and non-hodgkin lymphomas. Inhibition of beta catenin using small molecule inhibitors is currently being investigated in various tumor types. Recent studies suggest that targeting of the Wnt pathway and beta catenin may be promising targets in the therapy of acute myeloid leukemia.

Last updated: 2016-06-04 21:23:20 UTC
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Tier 1
SETD2
Variants
SETD2 any nonsense
SETD2 any frameshift
SETD2 any missense
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
T Lymphoblastic Leukemia/Lymphoma
Interpretation

SETD2 encodes a H3K36 trimethylase and loss of function mutations (missense, nonsense and frameshift mutations) have been reported in approximately 10% of acute myeloid leukemia, and 10% of acute lymphoblastic leukemia, including acute early T cell precursor acute lymphoblastic leukemia. SETD2 mutations appear to be enriched among cases of acute leukemia with rearrangements of MLL. Coexistence of two mutations in SETD2 has been described and together with recurrent loss of function mutations suggest this gene is acts as a tumor suppressor. The presence of loss of function mutations in SETD2 has been associated with global loss of H3K36me3. In addition, the presence of SETD2 mutations may be associated with therapy resistance.

Last updated: 2016-06-04 21:31:38 UTC
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Tier 1
CBLB
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Chronic Myeloid Leukemia
Acute Myeloid Leukemia
Interpretation

Casitas B lineage lymphoma b (CBL-B) belongs to the single-protein RING family of ubiquitin ligases. CBLB mutations have been reported in accelerated phase and blast phase chronic myelogenous leukemia but not chronic phase of chronic myelogenous leukemia. CBLB mutations have been reported together with TET2 mutations in some cases. CBLB mutations have not been reported in childhood acute lymphoblastic leukemia according to one study.

Last updated: 2016-06-04 21:34:46 UTC
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Tier 1
GATA2
Variants
GATA2 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Chronic Myeloid Leukemia
Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

GATA2 is a member of the GATA transcription factors which play a role in hematopoiesis. GATA2 mutations in the zinc finger domains have been described in accelerated phase and blasts phase chronic myelogenous leukemia as well as 5-10% of acute myeloid leukemia and familial syndromes with a predisposition to acute myeloid leukemia and myelodysplastic syndromes. Co-existing mutations in ASXL1 have been reported in a subset of patients with mutations in GATA2 and are believed to represent an important step in myeloid transformation, particularly to chronic myelomonocytic leukemia in young female patients. Other reports suggest that in cases of AML, GATA2 mutations have a higher prevalence among cases with biallelic CEBPA mutations and were not observed in cases with monoallelic CEBPA mutations. In general, the GATA2 pathogenic mutations are loss-of-function mutations (nonsense, frameshift, splice site mutations or missense mutations(codons 349-398)) and are believed to result in impairment of granulocyte differentiation. In MDS, GATA2 mutations may be associated with a poor prognosis. If clinical findings and family history are concerning for an inherited disorder, then genetic counseling may be helpful, if clinically indicated.

Last updated: 2019-08-28 14:54:00 UTC
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Tier 1
PIK3CA
Variants
PIK3CA E542K
PIK3CA E545K
PIK3CA H1047R
PIK3CA codon(s) 542, 545, 1047 any
PIK3CA exon(s) 10, 20, 21 any
Primary Sites
Blood
Bone Marrow
Tumor Types
Diffuse Large B Cell Lymphoma
Chronic Lymphocytic Leukemia
Interpretation

PIK3CA is the the p110 catalytic subunit-alpha of phosphatidylinositol 3 kinase. Activating mutations of PIK3CA occur in various types. PIK3CA mutations have been reported in approximately 8% of cases of diffuse large B cell lymphoma and are typically mutually exclusive of PTEN loss in that tumor type. PIK3CA mutations are very rare in chronic lymphocytic leukemia and believed to be absent in acute myeloid leukemia and myelodysplastic syndromes. PIK3CA mutations are potentially targetable in some settings and pathway inhibitors are currently under investigation .

Last updated: 2016-06-04 21:43:12 UTC
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Tier 1
WHSC1
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
B Lymphoblastic Leukemia/Lymphoma
Interpretation

WHSC1 (also known as NSD2 or MMSET) is a H3K36 methyltransferase that converts unmodified H3K36 to the monomethylated and dimethylated forms. NSD2 was recently found to show clonal and subclonal p.E1099K or p.D1125N activating alterations in 15% of t(12;21) ETV6-RUNX1–containing and 15% of TCF3-PBX1 contaning pediatric B-ALLs. The p.E1099K mutation appears to be less prevalent in other types of B-ALL(less than 5%) and both mutations appear to be absent in T-ALL, pediatric AML and adult ALL. In experimental models, increased H3K36 dimethylation and decreased unmodified H3K36 was associated with the NSD2 p.E1099K variant or the t(4;14) translocation( which leads to overexpression of NSD2). Overexpression of NSD2 in t(4;14)-positive multiple myeloma (MM) is also associated with globally increased levels of H3K36 dimethylation and decreased K27 trimethylation. NSD2 is considered to be a potential therapeutic target for a subset of cases of pediatric B-ALL.

Last updated: 2016-06-04 21:46:58 UTC
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Tier 1
PDGFRA
Variants
PDGFRA D842V
PDGFRA H650Q
PDGFRA N659S
PDGFRA R748G
PDGFRA T674I
PDGFRA Y849S
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Interpretation

Rearrangements of PDGFRA (including FIP1L1-PDGFRα) is a common abnormality among patients with chronic eosinophilic leukemia. In addition, activating mutations (eg, p.H650Q, p. N659S, p.R748G, p.Y849S) in PDGFRA have been reported in FIP1L1-PDGFRα-negative chronic eosinophilic leukemia and resistance mutations in PDGFRA (eg. p.D842V, p.T674I) have been reported in the setting of imatinib therapy for patients with FIP1L1-PDGFRα. These PDGFRA mutations have variable responses to the different available tyrosine kinase inhibitors.

Last updated: 2016-06-04 22:00:32 UTC
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Tier 1
KIT
Variants
KIT D816V
KIT exon(s) 11 any
KIT exon(s) 17 any
KIT exon(s) 8 missense
KIT exon(s) 9 missense
KIT exon(s) 10 missense
KIT any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Mast Cell Neoplasm
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

KIT(cKIT) mutations are present in approximately 8-25% of cases of acute myeloid leukemia and have a higher prevalence in the favorable cytogenetic risk group including core binding factor (CBF) AMLs (ie, (t(8;21)(q22;q22)(RUNX1-RUNX1T1), inv(16)(p13q22)(CBFB-MYH11)) or normal karyotype AML. Mutations of KIT in AML are most common in KIT exon 17 (within the activation loop of the tyrosine kinase domain) but may also occur in KIT exons 8 (extracellular portion of the receptor implicated in dimerization), 9-11 (juxtamembrane/transmembrane domains). The presence of KIT mutations has been reported to be associated with a poorer survival and/or higher risk of relapse than expected for patients with the t(8;21)(q22;q22)(RUNX1-RUNX1T1), and to a lesser extent, in inv(16) AML. KIT mutations are also important in systemic mastocytosis and various mast cell disorders; over 90% of cases of systemic mastocytosis carry mutations in exon 17 of KIT (most commonly D816V or rarely D816H, D816Y or other variants). In patients with mastocytosis, the KIT mutations may be detectable in non-mast cell hematopoietic cells. The KIT D816V mutation has been shown to be resistant to imatinib; other KIT mutations may show variable responses to imatinib. The KIT D816V mutant has been reported to be sensitive to other tyrosine kinase inhibitors. In the context of core binding factor AMLs, the KIT mutation status can help direct therapeutic management.

Last updated: 2018-11-12 20:41:34 UTC
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Tier 2
TET2
Variants
TET2 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Mast Cell Neoplasm
Acute Myeloid Leukemia
Primary Myelofibrosis
Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

Ten-Eleven Translocation-2 (TET2) encodes a dioxygenase that converts 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC) and promotes DNA demethylation. TET2 is a tumor suppressor gene and loss-of-function via mutations, deletion and IDH1/2 (Isocitrate Dehydrogenase 1 and 2) gene mutations is a common event in myeloid and lymphoid malignancies. TET2 is also present in about 10% of otherwise healthy elderly individuals with clonal hematopoiesis of indeterminate potential (CHIP) and in some patients with unexplained cytopenia but who do not satisfy diagnostic criteria for MDS, so-called clonal cytopenia with undetermined significance (CCUS). Mutations in TET2 occur in 50-60% of chronic myelomonocytic leukemias. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. TET2 mutations are also found in 20-40% of systemic mastocytosis, 36% of blastic plasamcytoid dendritic cell neoplasm, 12-32% of acute myeloid leukemia, 10-20% of primary myelofibrosis, 10-33% of myelodysplastic syndromes, 10% of myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), 22% of polycythemia vera, and 16% of essential thrombocythemia. TET2 mutations are absent in juvenile myelomonocytic leukemia and show a low prevalence (less than 5%) in pediatric AML. Among lymphoid neoplasms, TET2 mutations are reported in approximately 30% of angioimmunoblastic lymphomas and less than 15 % of other mature T cell lymphomas and mature B cell lymphomas. In general, the mutations in TET2 are typically loss of function variants (frameshift, missense, nonsense mutations) that may be monoallelic or biallelic and occur throughout the gene. TET2 mutations tend to be mutually exclusive of mutations in IDH1/IDH2. TET2 mutations are associated with unfavorable outcomes and shorter survival after hematopoietic stem cell transplantation in patients with myelodysplastic syndrome (PMID: 25092778). In acute myeloid leukemia with wild-type FLT3-ITD and normal karyotype or intermediate-risk cytogenetic abnormalities, TET2 mutations are associated with an unfavorable prognosis.

Last updated: 2019-08-28 14:54:00 UTC
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Tier 1
FBXW7
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
T Lymphoblastic Leukemia/Lymphoma
B Lymphoblastic Leukemia/Lymphoma
Chronic Lymphocytic Leukemia
Interpretation

FBXW7 is a ubiquitin protein ligase subunit which regulates levels of NOTCH, cyclin E, and other proteins. Loss-of-function mutations of FBXW7 lead to constitutive Notch1 pathway activation via inhibition of ubiquitin-mediated degradation of activated NOTCH1 and MYC. Mutations of FBXW7 include missense and frameshift mutations. FBXW7 have been reported in approximately 4-30% of cases of T-ALL less than 5% of cases of B-ALL, less than 5% of cases of CLL and appear to be very rare/absent in acute myeloid leukemia. According to some, but not all studies, NOTCH1 pathway activation by NOTCH1 mutations or FBXW7 mutations in TALL have been associated with an improved prognosis (in cases without concomitant RAS or PTEN mutations) compared to cases without mutations in NOTCH1 or FBXW7. FBXW7 mutations may occur alone or together with mutations in NOTCH1 (typically those in the heterodimerization domain and more rarely those in the PEST domain of NOTCH1). FBXW7 mutations may result in resistance to gamma secretase inhibitors according to some experimental studies.

Last updated: 2016-06-04 22:13:22 UTC
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Tier 3
TLR2
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Myelodysplastic Syndrome
Interpretation

Toll-like receptor (TLR) genes encode important components of innate immune system which is believed to play a role in the pathophysiology of myelodysplastic syndromes(MDS). Various TLR isoforms have been shown to be overexpressed in bone marrow CD34+ cells in MDS. In addition, the TLR2 p.F217S has been reported in approximately 10% of MDS patients. This variant is associated with enhanced activation of downstream signaling including NF-κB activity. TLR2 p.F217S may be associated with a higher frequency of chromosome 7 deletion in MDS as well. It is important to note that the TLR2 p.F217S variant has not been clearly established as a somatic variant and it is reported in the ESP database with an overall allele frequency of approximatly 0.3%. The potenital role of therapeutic targeting of TLR2 in MDS remains to be established.

Last updated: 2016-06-04 22:14:48 UTC
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Tier 1
IL7R
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
B Lymphoblastic Leukemia/Lymphoma
T Lymphoblastic Leukemia/Lymphoma
Interpretation

IL7R (Interleukin 7 receptor alpha) is required for normal lymphocyte development. Loss of function mutations are seen in severe combined immunodeficiency. More recently, heterozygous, somatic, activating mutations have been described in pediatric B-cell and T-cell acute lymphoblastic leukemia. These mutations are most frequently in-frame insertions and deletions in the transmembrane domain. In general, these mutations lead to the addition of a cysteine residue in the juxtamembrane domain, a change that is essential for the resultant constiutive activation of the receptor and JAK/STAT and mTOR pathways. Recently, non-cysteine mutations have been described in the transmembrane domain of IL7R, some of which are activating. IL7R mutations have been described in up to 6% of childhood B-ALL and are typically associated with aberrant CRLF2 expresssion and in up to 10% of childhood T-ALL/adult T-ALL and may co-exist with NOTCH1 mutations. These mutations are rare in adult AML(1%). The prognostic significance of these mutations remains to be elucidated. These mutations may have implications for targetted therapy. In addition to in frame exon 6 in/dels, activating mutations in exon 5 have been described in IL7R which are not detected by this assay.

Last updated: 2016-06-04 22:16:45 UTC
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Tier 2
CSF1R
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Interpretation

Mutations of CSF1R (M-CSF receptor) at codon 969 were initially reported in approximately 10-20% of cases of myelodsyplasia and acute myeloid leukemia including cases of chronic myelomonocytic leukemia and acute myeloid leukemia with monocytic differentiation. However, other studies have not been able to reproduce those findings. In addition to the Y969 mutation, other mutations in CSF1R as well as translocations involving CSF1R have been described in CSF1R. Interestingly, other mutations in CSF1R have also been reported to be associated with different disease, namely hereditary diffuse leukoenceophalopathy with spheroids.

Last updated: 2016-06-04 22:19:10 UTC
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Tier 1
NPM1
Variants
NPM1 codon(s) 288 frameshift
NPM1 codon(s) 290 frameshift
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

Mutations of NPM1 have been reported in approximately 25-35% of cases of acute myeloid leukemia (AML). The mutations of NPM1 are frameshift mutations in the C-terminus of the protein that alter the C-terminal amino acid sequence and are associated with aberrant cytoplasmic localization of the protein. NPM1 mutations in AML are typically associated with a normal karyotype and may co-exist with FLT3 mutations. The presence of NPM1 mutations has been associated with improved complete remission rates, but not necessarily overall survival, in multivariate analysis including assessment of the variety of more recently discovered mutations that may be present in AML. In addition, cytogenetically normal AML with mutated NPM1, without FLT3 ITD or mutated DNMT3A, has been considered to be a favorable genetic risk group according to some studies, although other studies suggest that coexistant mutations in IDH1 or IDH2 may be required for the favorable risk effect of NPM1.

Last updated: 2018-11-12 20:40:30 UTC
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Tier 2
PIM1
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Interpretation

PIM1 is a member of the PIM family of proteins which are proto-oncogenes, serine-threonine kinases with increased expression in a variety of malignancies. PIM1 expression appears to be up-regulated by STAT5, and has been found to be over-expressed in primary AML blast samples. In particular, PIM1 has associated with FLT3 mediated leukemogenesis in FLT3-ITD AML. PIM1 expression was noted to be 25-fold higher than in FLT3-ITD samples, as compared to wild type FLT3 (WT) AML samples. The PIM kinases, therefore, represent potential therapeutic targets in AML, particularly in those cases harboring FLT3-ITD mutations. According to one study, the small molecule inhibitor of PIM1, AR00459339, alone and in combination with a FLT3 inhibitor (AR00454200), resulted in significant cytotoxicity in FLT3-ITD cell lines and patient samples that strikingly parallels the effects of FLT3 inhibition. A variety of mutations have been reported throughout PIM1 in various types of malignancy including hematopoietic tumors, but PIM1 mutations appear to be extremely rare in acute myeloid leukemia and myelodysplasia.

Last updated: 2016-06-04 22:29:01 UTC
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Tier 2
IKZF1
Variants
IKZF1 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
B Lymphoblastic Leukemia/Lymphoma
Acute Leukemia of Unspecified Cell Type
Acute Myeloid Leukemia
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

IKZF1(Ikaros) is a transcriptional regulator of B cell development and is believed to have tumor suppressor-like properties. Deletions (whole gene and/or partial gene deletions) of IKZF1 have been reported in approximately 15-28% of BCR-ABL1-Negative_B-cell ALL, 70-90% of BCR-ABL1-Positive B-cell ALL. IKZF1 mutations are also found in approximately 40% of "Ph-like" ALL. Loss of functions mutations (missense, nonsense, frameshift mutations) have also been reported in IKZF1 in ALL and appear to be much less common (less than 5% of cases) than deletions. Deletions and mutations in IKZF1 have been associated with adverse prognosis and greater risk of relapse.

Last updated: 2019-08-28 14:54:01 UTC
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Tier 2
CUX1
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Chronic Lymphocytic Leukemia
Chronic Myelomonocytic Leukemia
Interpretation

CUX1(CUTL1, CDP) is a transcription factor proposed to act as a haploinsufficient myeloid tumor suppressor that maps to the commonly deleted segment in cases of myeloid malignancies with complete or partial loss of chromosome 7; such cases show reduced expression of CUX1. In addition, loss of function (missense, nonsense, frameshift) mutations of CUX1, occuring throughout the gene, have been described in a variety of cancer types; they occur in up to 10% of chronic myelomonocytic leukemia and are rare (less than 5%) in acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative neoplasms and chronic lymphocytic leukemia. When loss of function mutations do occur in CUX1, they do not coexist with monosomy 7 or del7q, consistent with its role as a haploinsufficient tumor suppressor gene in most cases; nevertheless, compound heterozygous loss of function mutations in CUX1 have been described in rare cases. In MDS and MDS/MPN, both CUX1 inactivation and −7/del(7q) have been associated with poorer overall survival according to some studies. CUX1 deficiency has been reported to activate phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition in some models.

Last updated: 2016-06-04 22:35:54 UTC
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Tier 2
LUC7L2
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Interpretation

LUC7L2 is thought to be an RNA binding protein and component of the RNA splicing machinery. Recent studies suggest that it may be a recurrent mutation in a subset of patients with AML and/or MDS although its prevalence appears to be low (less than 5%). In addition, the significance of LUC7L2 mutations is uncertain although in some reported cases it has been associated with disease progression. Further study is required.

Last updated: 2016-06-04 22:36:55 UTC
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Tier 2
BRAF
Variants
BRAF V600D
BRAF V600E
BRAF V600K
BRAF V600R
BRAF codon(s) 600 any
BRAF any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Leukemia of Unspecified Cell Type
Acute Myeloid Leukemia
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Chronic Lymphocytic Leukemia
Diffuse Large B Cell Lymphoma
Interpretation

B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. Mutations of B-RAF have been described in up to 100% of Hairy cell leukemia, 40-70% of Langerhans cell histiocytosis, approximately 50% of Erdheim-Chester disease, approximately 5% of diffuse large B cell lymphoma and plasma cell neoplasms and less than 5% of chronic lymphocytic leukemia. While some reports have found that 10-20% of cases of acute leukemias (ALL or AML) may have BRAF mutations, other reports have described no BRAF in those diseases or in myeloid diseases such as MDS or CML. The hotspot for mutations in BRAF is at codon Val600 and these are activating mutations. The most common activating mutation is p.Val600Glu(V600E). Various B-Raf inhibitors(Vemurafenib, Dabrafenib) have been FDA approved for therapy for some tumor types in certain clinical settings.

Last updated: 2018-11-12 20:40:44 UTC
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Tier 1
EZH2
Variants
EZH2 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Atypical Chronic Myeloid Leukemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

EZH2 encodes the histone methyltransferase subunit of the polycomb repressive complex 2 (PRC2) that leads to H3K27me3 and promotes transcriptional repression. EZH2 loss of function mutations (nonsense, frameshift mutations, occasionally occurring as homozygous mutations) may occur throughout the gene and have been reported in less than 10% of patients with acute myeloid leukemia, myelodysplasia, atypical chronic myelogenous leukemia, primary myelofibrosis and up to 12% of patients with chronic myelomonocytic leukemia. EZH2 loss of function mutations may be more frequent (15%) among cases of T cell acute lymphoblastic leukemia. EZH2 mutations have been independently associated with adverse prognosis in MDS and MDS/MPN. Therapeutic targeting of EZH2 is currently under study for some types of lymphoma and solid tumors.

Last updated: 2019-08-28 14:54:01 UTC
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Tier 2
RAD21
Variants
RAD21 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Chronic Myeloid Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

RAD21 belongs to the cohesin complex family of genes that encode protein subunits of the cohesion complex, which regulates chromosomal segregation. is a member of the cohesin complex that regulates chromosome segregation during meiosis and mitosis. Loss of function mutations of RAD21 have been described throughout the gene in approximately 1% of cases of myelodysplasia, 1-5% of acute myeloid leukemia (AML), 1% of chronic myeloid leukemia and tend to be mutually exclusive of other mutations in the other components of the cohesin complex (ie, STAG1, SMC3, STAG2, SMC1A). In AML, mutations in the cohesin complex genes tend to be associated with mutations in NPM1. Cohesin complex mutations do not have clear prognostic impact in AML. Cohesin complex mutations are associated with an unfavorable prognosis in myelodysplastic syndrome, and are more frequently found in patients with high IPSS scores and secondary acute myeloid leukemia.

Last updated: 2019-08-28 14:54:01 UTC
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Tier 1
JAK2
Variants
JAK2 V617F
JAK2 exon(s) 12 insertion
JAK2 exon(s) 12 deletion
JAK2 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Essential Thrombocythemia
Primary Myelofibrosis
Polycythemia Vera
Acute Leukemia of Unspecified Cell Type
Acute Myeloid Leukemia
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

JAK2 is a non-receptor tyrosine kinase that mediates signaling via the JAK-STAT pathway. The somatic, activating mutation V617F in the pseudokinase domain of JAK2 has been reported in over 90% of patients with polycythemia vera, 40-70% of essential thrombocythemia, 40-60% of primary myelofibrosis and 50% of MDS/MPN with Ring Sideroblasts and Thrombocytosis. JAK2 mutations have also been reported in CHIP. The small percentage of cases of polycythemia vera that do not carry the JAK2 V617F mutation have somatic, activating mutations in JAK2 exon 12 which typically affect the region encompassing codons 536-547 and are in-frame deletions/insertions, duplications of 8-12 amino acids or missense mutations. Mutations in JAK2 are typically mutually exclusive with mutations in the thrombopoietin receptor (MPL) and calreticulin (CALR), but JAK2 mutations may co-exist with mutations in other genes (ie, IDH1, SF3B1, TET2, ASXL1, etc). Ruxolitinib is a JAK2 inhibitor that has been approved for use in patients with intermediate- and high-risk primary myelofibrosis and is under study in other JAK2+ MPNs. Other JAK2 inhibitors (eg, Pacritinib) are also in various stages of study.

Last updated: 2018-11-12 20:41:32 UTC
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Tier 1
PAX5
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
B Lymphoblastic Leukemia/Lymphoma
Interpretation

PAX5 is an important transcription factor in B cell development. Somatic deletions, rearrangements and mutations of PAX5 are seen in approximately 30% of B-ALL. Mutations most commonly include missense and frameshift mutations throughout the gene which typically lead to decreased transcriptional activation by PAX5. A frequent site of mutation is Pro80. Interestingly, a germline variant in PAX5 has been recently described (p.Gly183Ser) that is linked to family history of B-ALL and development of leukemia when associated with 9p deletion(loss of heterozygosity) and retention of the mutant allele in tumor cells; mutations at this codon have also been reported in tumors as a somatic alteration.

Last updated: 2016-06-04 23:05:51 UTC
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Tier 1
ABL1
Variants
ABL1 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Acute Leukemia of Unspecified Cell Type
Acute Myeloid Leukemia
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

ABL1 kinase domain mutations in Philadelphia chromosome positive acute lymphoblastic leukemia and chronic myelogenous leukemia are associated with resistance to some types of tryosine kinase inhibitor therapy. The various mutations span several hundred amino acids (M237 thru E507) and vary in their response to later generation tyrosine kinase inhibitors.

Last updated: 2019-08-28 14:54:01 UTC
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Tier 2
NOTCH1
Variants
NOTCH1 exon(s) 26 missense
NOTCH1 exon(s) 27 missense
NOTCH1 exon(s) 34 frameshift
NOTCH1 exon(s) 34 nonsense
NOTCH1 exon(s) 34 missense
NOTCH1 exon(s) 26 insertion
NOTCH1 exon(s) 26 deletion
NOTCH1 exon(s) 27 insertion
NOTCH1 exon(s) 27 deletion
Primary Sites
Blood
Bone Marrow
Tumor Types
T Lymphoblastic Leukemia/Lymphoma
Acute Leukemia of Unspecified Cell Type
Acute Myeloid Leukemia
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

NOTCH1 encodes a member of the NOTCH family of proteins, which is a group of transmembrane receptors involved in the Notch signaling pathway. Notch signaling regulates cell fate decisions during development, and plays a crucial role in T cell development. Activating mutations of NOTCH1 including missense mutations and inframe inserstions/deletions in the heterodimerization(HD) domains either alone or together with missense, nonsense or frameshift (in/del) mutations in the C terminal PEST domain have been described in approximately 50% of cases of T-ALL. The HD domain or PEST domain mutations may occur together in cis (on the same allele) in ALL. NOTCH1 mutations are very rare in AML. However, NOTCH1 mutations are present in about 27% patients with T-myeloid mixed-phenotypeacute leukemia. The potential utility of therapeutic targeting of activating NOTCH1 mutations in these diseases remains to be elucidated.

Last updated: 2018-11-12 20:40:47 UTC
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Tier 1
GATA3
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
T Lymphoblastic Leukemia/Lymphoma
Interpretation

GATA 3 is a transcription factor important in T cell development and is known to be mutated in certain syndromes(hypoparathroidism, deafness, renal dysplasia). Missense, frameshift and insertion/deletion mutations in the zinc finger domain have been reported in 10-15% of early T cell precursor ALL and may be associated with biallelic mutations or concomitant deletion of the second allele.

Last updated: 2016-06-04 23:29:35 UTC
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Tier 1
PTEN
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
T Lymphoblastic Leukemia/Lymphoma
Interpretation

PTEN is a lipid and protein phosphatase that negatively regulates the PI3K/AKT/mTOR pathway. PTEN has been reported to show nonsense and frameshift mutations in approximately 10% of adult T cell ALL patients. PTEN mutations may occur together with large deletions of PTEN which are not detected by this assay. PTEN abnormalities are thought to be more frequent in NOTCH1/FBXW7 unmutated T-ALL and appear to be mutually exclusive of NRAS/KRAS mutations in T-ALL. PTEN alterations are associated with reduced or absent protein expression and may be associated with a poor prognosis in adult T cell ALL, but not pediatric T-ALL, according to some studies. PTEN alterations appear to be infrequent among myeloid malignancies.

Last updated: 2016-06-04 23:31:10 UTC
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Tier 1
NT5C2
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
B Lymphoblastic Leukemia/Lymphoma
T Lymphoblastic Leukemia/Lymphoma
Interpretation

The cytosolic 5'-nucleotidase II gene (NT5C2), encodes a 5'-nucleotidase that is responsible for the inactivation of nucleoside-analog chemotherapy drugs. NT5C2 dephosphorylates and inactivates 6-thioinositol monophosphate and 6-thioguanosine monophosphate which mediate the cytotoxic effects of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), two nucleoside analogs commonly used in the treatment of ALL. Activating mutations of NT5C2 have been reported in 19%of relapsed T cell ALLs and 3-10% of relapsed B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine, suggesting that relapse-specific mutations in NT5C2 may act as a mechanism of resistance to 6-MP and a genetic driver of relapse in ALL.

Last updated: 2016-06-05 00:57:49 UTC
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Tier 1
SMC3
Variants
SMC3 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

SMC3 is a member of the cohesin complex and has been found to be mutated in approximately 1% of acute myeloid leukemia and 1% myelodysplastic syndromes. The mutations of SMC3 described tend to be missense mutations that occur throughout the gene. Mutations of the various members of the cohesin complex appear to occur in a mutually exclusive manner. Cases of AML with mutations of the cohesin complex may be associated with mutations of NPM1. Currently there does not appear to be any clear prognosistic impact of cohesin complex gene mutations in AML. Cohesin complex mutations are associated with an unfavorable prognosis in myelodysplastic syndrome, and are more frequently found in patients with high IPSS scores and secondary acute myeloid leukemia.

Last updated: 2019-08-28 14:54:01 UTC
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Tier 2
WT1
Variants
WT1 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

WT1 encodes for a transcription factor containing an N-terminal transactivation domain and a C-terminal zinc-finger domain necessary for the development of the urogenital system. The precise roles of WT1 in normal and malignant hematopoiesis remain uncertain. New emerging supports a novel role of WT1 in the regulation of epigenetic programs through its interaction with TET proteins in the 5=hydroxymethylation of cytosines. WT1 mutations are found in 6% of acute myeloid leukemia overall, and about 8-13% in cytogenetically normal AML. Higher frequencies are present in biallelic CEBPA mutated acute myeloid leukemia (14%), followed by t(15;17)/PML-RARA (11.0%), and FLT3-ITD (8.5%,). WT1 mutations are associated with younger age in AML. WT1 mutations are typically putative loss of function mutations and most frequently occur in exon 7 or exon 9. About 75% of these mutations are frameshift, and the remaining are missense, nonsense, splice site or inframe indel mutations. In some cases two or more mutations in WT1 may occur. In addition, WT1 mutations may coexist with mutations in NPM1, FLT3, among others. WT1 is overexpressed in the majority of AML, giving rise to the concept that it may act as both a tumor suppressor and oncogene, depending on the context. Several studies showed that WT1 mutations are associated with a worse prognosis in cytogenetically normal acute myeloid leukemia, although one study including patients from three German-Austrian AML study protocols demonstrated no association with overall survival or relapse-free survival. Given its over-expression in AML, clinical trials employing peptide vaccination strategy against WT1 has been ongoing in AML patients.

Last updated: 2019-08-28 14:54:01 UTC
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Tier 1
SF1
Variants
SF1 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

SF1 is a member of the spliceosome machinery and missense mutations have been described in approximately 1% of myeloid neoplasms including myelodysplasia, acute myeloid leukemia and myeloproliferative neoplasms.

Last updated: 2019-08-28 14:54:01 UTC
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Tier 1
EED
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
T Lymphoblastic Leukemia/Lymphoma
Chronic Myelomonocytic Leukemia
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Interpretation

EED is a component of the polycomb repressor complex 2 (PRC2). Missense and frameshift mutations have been described in T cell acute lymphoblastic leukemia and may be enriched in the early T cell precursor subtype of that disease(found in appromimately 5% of such cases). In addition, mutations of EED have been described in, overall, less than 5% of myeloid neoplasms including cases of CMML, AML and MDS. EED mutations tend to be exclusive of mutations in EZH2, another component of PRC2. Deletions of EED have also been described which are not detected by this assay.

Last updated: 2016-06-05 01:00:57 UTC
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Tier 1
ATM
Variants
Primary Sites
Blood
Bone Marrow
Lymph Node
Tumor Types
Chronic Lymphocytic Leukemia
Mantle Cell Lymphoma
T Cell Lymphoproliferative Disorder
Interpretation

The ataxia telangiectasia mutated (ATM) gene is important in the cellular response to DNA double stranded breaks. ATM genetic abnormalities include deletions and mutations which may occur alone or together. ATM mutations have been reported to occur in approximately 35% of chronic lymphocytic leukemia; biallelic ATM inactivation (deletions and mutations) are associated with a poor outcome in some setttings compared to monoallelic ATM deletion or mutation in CLL. The ATM mutations occur throughout the gene and are putative loss of function variants (missense, nonsense and frameshift mutations). ATM mutations have also been reported in other types of lymphoma including mantle cell lymphoma (50%) and T cell prolymphocytic leukemia (46%).

Last updated: 2016-06-05 01:03:17 UTC
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Tier 2
CBL
Variants
CBL any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Chronic Myelomonocytic Leukemia
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

CBL (casitas-B-lineage lymphoma) gene mutations have been identified in approximately 15% of chronic myelomonocytic leukemia, 15% of juvenile myelomonocytic leukemia, 15% of secondary AML(from MDS or MDS/MPN overlap syndrome) and rare or absent in polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic eosinophilic leukemia and MDS. Also, CBL mutations are found in only 1% of de novo acute leukemias and tend to be associated with core binding factor acute myeloid leukemia (AML) among AML cases. CBL is a Ras pathway gene and has been associated with hereditary myeloid disorders. CBL ubiquitinylates and degrades activated receptor and non-receptor tyrosine kinases via the E3-ligase activity of its RING domain. CBL also acts as an adaptor for downstream cell signal transduction, via its tyrosine kinase binding domain. Most variants of the CBL protein are missense substitutions in the zinc binding RING domain (amino acids 366-420) (exons 8-9) that abrogate CBL ubiquitin ligase activity but retain other functions. Pathogenic mutations are believed to be oncogenic by a variety of potential mechanisms including increased Ras pathway activation, aberrant phosphoSTAT5 and/or increased KIT expression in different cellular contexts. Occasionally, two CBL mutations may be present or CBL mutations may be associated with uniparental disomy. In addition, CBL mutations may occur together with mutations in other genes ( RUNX1, ASXL1, TET2 or EZH2 ). According to some studies, mutations of CBL may be associated with reduced overall survival in MDS.

Last updated: 2019-08-28 14:54:01 UTC
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Tier 1
ETV6
Variants
ETV6 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
T Lymphoblastic Leukemia/Lymphoma
Acute Leukemia of Unspecified Cell Type
Acute Myeloid Leukemia
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

ETV6 is a transcriptional repressor and is frequently involved in translocations with a variety of different partner genes in a range of hematologic malignancies. Mutations of ETV6 have been described in <5% of myelodysplastic syndromes and appear to be more frequent (ie, 10-24% of cases) in early T cell precursor type (immature) acute lymphoblastic leukemias. In addition, ETV6 mutations have been reported in association with hereditary myeloid disorders. These mutations occur throughout the gene and typically correspond to loss of function mutations (nonsense and frameshift mutations). ETV6 mutations may occasionally occur in a homozygous/hemizygous manner and tend to occur with mutations in NOTCH1 in lymphoblastic leukemia. In MDS, ETV6 mutations have been independently associated with an adverse prognosis. If clinical findings and family history are concerning for the presence of an inherited disorder, then genetic counseling may be helpful, if clinically indicated.

Last updated: 2019-08-28 14:54:01 UTC
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Tier 2
KRAS
Variants
KRAS codon(s) 12, 13, 61, 117, 146 any
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Myelodysplastic Syndrome
B Lymphoblastic Leukemia/Lymphoma
T Lymphoblastic Leukemia/Lymphoma
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

KRAS is a well known proto-oncogene that belongs to the small GTPase family and functions as a central mediator of downstream growth factor receptor signaling, with a critical role for cell proliferation and survival. Pathogenic mutations in KRAS typically occur in codons 12-13 of exon 2 and codon 61 of exon 3; however, other, non-canonical, pathogenic mutations in KRAS have also been reported in acute myeoid leukemia. KRAS mutations have been described in approximately 3-15% of acute myeloid leukemia, 8-20% of chronic myelomonocytic leukemia, 14% of juvenile myelomonocytic leukemia, 8% of blastic plasmacytoid dendritic cell neoplasm 4% of patients with myelodysplastic syndrome, 2% of primary myelofibrosis, 12% of B cell acute lymphoblastic leukemia (often associated with MLL rearrangement) and 1-2% of T cell acute lymphoblastic leukemia. Investigation into the targetability of this pathway in leukemia has been attempted in some disease models.

Last updated: 2018-11-12 20:40:39 UTC
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Tier 1
PRPF40B
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Interpretation

PRPF40B is a member of the RNA splicing machinery which has been reported to be rarely mutated (less than 5%) among cases of acute myeloid leukemia, myelodysplasia, chronic myelomonocytic leukemia and myeloproliferative neoplasms. Mutations in PRPF40B are typically missense mutations that may be located throughout the gene. PRPF40B mutations tend to be exclusive of other mutations in the spliceosome pathway.

Last updated: 2016-06-05 01:08:34 UTC
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Tier 2
SH2B3
Variants
SH2B3 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
T Lymphoblastic Leukemia/Lymphoma
B Lymphoblastic Leukemia/Lymphoma
Acute Leukemia of Unspecified Cell Type
Acute Myeloid Leukemia
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

SH2B3 encodes the lymphocyte adaptor protein (LNK) which attenuates JAK2 activation and negatively regulates the signaling of the thrombopoietin receptor (MPL) and the erythropoietin receptor. LNK has also shown to bind and regulate mutant signaling molecules found in myeloproliferative neoplasms (MPNs) like MPL-W515L and JAK2-V617F. Several acquired SH2B3 frameshift and missense mutations in the pleckstrin homology domain and NH2-terminal region have been reported in myeloproliferative neoplasms. Somatic mutations of SH2B3 are infrequent in MPN and reported in ~5 to 7% of MPN patients. These mutations can be found in all MPN subtypes and co-exist with other driver genes. In one study, SH2B3 mutations are associated with JAK2, CALR and MPL mutations in 50%, 18% and 13.6% of positive cases. All identified mutations were found throughout the gene, without evidence of a hot spot. SH2B3 mutations may be enriched in blast phase disease with a frequency up to 13% of such cases. Also, approximately 1% of T cell and B cell acute lymphoblastic leukemias have been shown to carry homozygous frameshift or nonsense mutations in SH2B3. Partial deletions of SH2B3 have also been reported in ALL. In addition, the T allele of a nonsynonymous single-nucleotide polymorphism (SNP), rs3184504 (p;W262R, c.784T>C), in exon 2 of the SH2B3 gene has been reported to be more prevalent among JAK2V617F-positive patients than control patients or JAK2 wild type patients. Loss of function mutations in SH2B3 have been shown to lead to increased JAK2/STAT3 signaling and cell proliferation.

Last updated: 2020-10-06 21:21:05 UTC
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Tier 2
PTPN11
Variants
PTPN11 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Myelodysplastic Syndrome
B Lymphoblastic Leukemia/Lymphoma
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

PTPN11 encodes SHP2, a member of the non-receptor protein tyrosine phosphatase (PTP) family that regulates growth factor and cytokine signaling and plays a key role in the proliferation and survival of hematopoietic cells. PTPN11 mutation is directly associated with the pathogenesis of Noonan syndrome and childhood leukemias. Despite its direct function in protein dephosphorylation, SHP2 plays an overall positive role in transducing signals. Germline and somatic mutations that result in increased activity of PTPN11 have been described in Noonan's syndrome (approximately 50%), juvenile myelomonocytic leukemia (35-42%), pediatric and adult myelodysplasic syndromes (4-10%), B cell acute lymphoblastic leukemia (5-10%), as well as pediatric and adult acute myeloid leukemia (5-10%). These gain of function mutations most often occur as heterozygous missense mutations located in exon 3 (SH2 domain) or exon 13 (phosphatase domain) . Within cases of juvenile myelomonocytic leukemia, mutations of PTPN11 tend to be exclusive of mutations in RAS, CBL and NF-1. PTPN11 mutations in adult AML are associated with a normal karyotype and concurrent NPM1 mutation, but no alteration of the FLT3. In one study, myelodysplastic syndromes with PTPN11 mutations were shown to have a worse overall survival. Small molecule inhibitors of PTPN11 are currently being developed.

Last updated: 2019-08-28 14:54:01 UTC
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Tier 1
FLT3
Variants
FLT3 D835A
FLT3 D835E
FLT3 D835H
FLT3 D835N
FLT3 D835V
FLT3 exon(s) 14 insertion
FLT3 exon(s) 15 insertion
FLT3 codon(s) 835 missense
FLT3 Y842C
FLT3 codon(s) 839 missense
FLT3 codon(s) 842 missense
FLT3 codon(s) 691 missense
FLT3 codon(s) 676 missense
FLT3 codon(s) 697 missense
FLT3 codon(s) 835 any
FLT3 codon(s) 839 any
FLT3 codon(s) 842 any
FLT3 exon(s) 20 any
FLT3 exon(s) 17 any
FLT3 exon(s) 14-23 any
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
T Lymphoblastic Leukemia/Lymphoma
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

FLT3 is a receptor tyrosine kinase important in hematopoietic cell proliferation and differentiation. In-frame, FLT3 internal tandem duplications (ITD), which show a wide range of number of nucleotides duplicated and/or inserted (eg, 18-204 bp), affect exons 14 and 15 in the FLT3 juxtamembrane/tyrosine kinase domain and have been reported in 20-30% of patients with acute myeloid leukemia. FLT3 ITDs usually occur in cases of AML with a normal karyotype and but may also occur in cases with chromosome abnormalities including t(15;17) or other cytogenetic groups. Individuals with FLT3 mutations are more likely to have AML than MDS and FLT3 mutations in MDS are associated with a poor prognosis. Functional studies have shown that FLT3 ITDs are ligand-independent, gain-of-function mutations. In addition, activating mutations at codon D835 in exon 20 (A-loop of the tyrosine kinase domain, TKD) of FLT3 have been reported in approximately 7-10% of AML. The FLT3 D835 mutations are also ligand-independent, gain-of-function mutations. FLT3 ITD and D835 mutations tend to occur in a mutually exclusive manner; however, the FLT3 D835 mutation or other mutations in the A-loop(eg, D839, Y842) may occur as an acquired resistance mutation in the setting of patients with FLT3 ITD mutations being treated with targeted therapy. In addition, variants at codon N676 and in exon 17 F691, G697 have been associated with resistance to FLT3 targeted therapy. The presence of FLT3 ITD mutation in young patients with AML and normal cytogenetics is thought to be associated with a poor prognosis. On the other hand, the prognostic significance of the FLT3 D835 and TKD mutations appears less clear. More recently, therapeutic targeting of FLT3 in combination with other chemotherapy is available in certain settings for acute myeloid leukemia with FLT3 ITD or TKD mutations. Lastly, in T cell acute lymphoblastic leukemia, up to 20% of cases have been reported to show a FLT3 mutation (TKD or ITD) and are often associated with an ETP(early T cell precursor) phenotype. In addition, FLT3 mutations have also been reported in up to 15% of B-ALL cases ("Ph-like phenotype") and may also be associated with hyperdiploidy and MLL rearrangement. Targetting FLT3 in acute lymphoblastic leukemia therapy may also be possible in some settings.

Last updated: 2018-11-12 20:41:30 UTC
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Tier 2
PDS5B
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Myelodysplastic Syndrome
Interpretation

PDS5B is a functional component of the cohesin complex which is very rarely mutated in myeloid neoplasms.

Last updated: 2016-06-05 01:41:59 UTC
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Tier 1
IDH2
Variants
IDH2 R140Q
IDH2 R172K
IDH2 codon(s) 140, 172 any
IDH2 codon(s) 140 missense
IDH2 codon(s) 172 missense
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Primary Myelofibrosis
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

IDH2 is a mitochondrial enzyme involved in citrate metabolism. Mutations at Arg140 and Arg172 of IDH2 are typically heterozygous mutations and considered gain of function mutations that lead to increased levels of 2-hydroxyglutarate which is believed to alter epigenetic regulation (ie, DNA methylation) in AML. Mutations of IDH2 appear to be mutually exclusive of mutations in TET2, another gene involved in regulation of DNA methylation, and also exclusive of mutations in IDH1. Mutations of IDH2 have been shown to lead to increased DNA methylation in AML. IDH2 mutations have been reported in 10-20% of AML and are often associated with a normal karyotype. IDH2 mutations have been reported in less than 5% of cases of MDS and less than 10% of myeloproliferative neoplasms. The prognostic impact of IDH2 mutations in AML appears uncertain due to conflicting reports. In the setting of essential thrombocytosis, primary myelofibrosis and MDS, the presence of IDH2 mutations is associated with reduced survival. Therapeutic targeting with an FDA approved mutant IDH2 inhibitor (enasidenib (AG-221)) has been reported for patients with relapsed or refractory IDH2-mutated AML.

Last updated: 2018-11-12 20:41:32 UTC
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Tier 1
CREBBP
Variants
Primary Sites
Blood
Bone Marrow
Lymph Node
Tumor Types
B Lymphoblastic Leukemia/Lymphoma
Diffuse Large B Cell Lymphoma
Follicular Lymphoma
Interpretation

CREB binding protein (CREBBP) is considered to be an epigenetic regulator with diverse functions that include acetyltransferase activity, scaffolding function for transcription factor complexes and ubiquitin ligase activity. CREBBP mutations may occur as germline variants in Rubinstein Taybi syndrome and as somatic variants where they have been described in lymphoid malignancies. Missense, frameshift and nonsense mutations of CREBBP have been reported in 13-43% of B cell acute lymphoblastic leukemia and tend to occur in the HAT domain that is encoded by exons 18 through 29; more specifically, the missense mutations typically cluster in exons 25-27 of the HAT domain, however, mutations in other regions in the protein have been reported and may be important. CREBBP mutations have also been described in diffuse large B cell lymphoma and follicular lymphoma. Deletions/loss of heterozygosity of CREBBP has been described in ALL but are not detectable by this assay. Mutations of CREBBP appear to predominate in hyperdiploid B cell ALL, especially in such cases associated with disease relapse.

Last updated: 2016-06-05 01:47:14 UTC
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Tier 1
CTCF
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
T Lymphoblastic Leukemia/Lymphoma
Myelodysplastic Syndrome
Interpretation

CTCF is a zinc finger protein involved in a variety of cell functions. Mutations of CTCF including missense, nonsense and frameshift mutations occur throughout the gene and have been reported in approximately 5% of acute megakaryoblastic leukemia, 2% of transient abnormal myelopoiesis, less than 5% of AML, less than 5% of MDS and less than 5% cases of ALL.

Last updated: 2016-06-05 01:48:59 UTC
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Tier 1
PRPF8
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Myelodysplastic Syndrome
Acute Myeloid Leukemia
Interpretation

PRPF8 (Pre-MRNA Processing Factor 8) is a component of the RNA splicing machinery. Somatic PRPF8 mutations have been reported in less than 5% of cases of myelodysplastic syndrome/secondary AML and PRPF8 mutation status may be used, together with other clinical and molecular markers, in some prognostic models of MDS .

Last updated: 2016-06-05 01:50:01 UTC
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Tier 1
TP53
Variants
TP53 copy number loss
Primary Sites
Blood
Bone Marrow
Lymph Node
Tumor Types
Acute Leukemia of Unspecified Cell Type
Acute Myeloid Leukemia
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

TP53 is a well known tumor suppressor gene that is mutated in wide variety of cancers. Loss of function mutations (missense, nonsense and frameshift mutations) of TP53 have been described in 10-20% of CLL cases and TP53 gene defects tend to be enriched among cases with unmutated IGH variable regions; in some series, TP53 mutations have been reported in approximately 15%-18% of IGHV unmutated CLL cases . TP53 mutations appears to be less common in other types of CLL (eg, less than 5% of IGHV3-21-expressing CLL carried a TP53 defect according to one study). Mutations of TP53 in CLL have been found together with del17p and mutations in other genes such as NOTCH1 and SF3B1. Mutations and deletions of TP53 appear to represent adverse prognostic markers in chronic lymphocytic leukemia.

Last updated: 2018-11-12 20:39:01 UTC
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Tier 2
IKZF3
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Chronic Myeloid Leukemia
Interpretation

IKZF3 is a member of the IKAROS family of transcription factors which are important in lymphoid development. Missense and frameshift mutations of IKZF3 have been reported in approximately 10% of chronic phase and matched blast phase of CML , approximately 10% of blastic plasmacytoid dendritic cell neoplasms and rare cases of acute lymphoblastic leukemia.

Last updated: 2016-06-05 02:00:23 UTC
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Tier 1
STAT3
Variants
Primary Sites
Blood
Bone Marrow
Lymph Node
Tumor Types
T-Cell LGL Leukemia
T Cell Lymphoproliferative Disorder
NK Cell Lymphoproliferative Disorder
Interpretation

Signal transducer and activator of transcription 3 gene (STAT3) plays an important role in the JAK/STAT signaling pathway induced by cytokine and growth factor receptor activation. STAT3 mutations have been reported in approximately 40% of cases of T-cell large granular lymphocytic leukemia and one third of NK cell lymphoproliferative disorders; these mutations are typically missense mutations or inframe insertions mutations in exons 20 and 21 which encode the Src homology 2 (SH2) domain that mediates the dimerization and activation of STAT protein; these mutations are typically associated with increased transcriptional activity. In addition, the presence of STAT3-mutant T-LGL clones may be found in a subset of patients with aplastic anemia and/or myelodysplastic syndrome. Therapeutic targetting of STAT3 is currently under investigation in various settings.

Last updated: 2016-06-05 02:01:56 UTC
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Tier 1
CD79B
Variants
Primary Sites
Blood
Bone Marrow
Lymph Node
Tumor Types
Diffuse Large B Cell Lymphoma
Interpretation

CD79B is a component of the cell surface B cell receptor complex and is upstream of the NFkB signaling pathway. CD79B mutations at Tyr196 have been reported in approximately 20% of primary testicular diffuse large B cell lymphomas and approximately 10-15% of diffuse large B cell lymphomas overall. CD79B mutations are typically associated with increased cell surface expression of CD79B due to attenuation of the usual negative feedback by LYN kinase. CD79B mutations have been reported to coexist with MYD88 mutations and may be enriched in the activated B cell type of diffuse large B cell lymphoma. The potential for therapeutic targeting of this pathway is currently under investigation.

Last updated: 2016-06-05 02:02:54 UTC
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Tier 1
SRSF2
Variants
SRSF2 codon(s) 95 missense
Primary Sites
Blood
Bone Marrow
Tumor Types
Chronic Myelomonocytic Leukemia
Myelodysplastic Syndrome
Acute Myeloid Leukemia
Primary Myelofibrosis
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

SRSF2 is a member of the serine/arginine-rich family of pre-mRNA splicing factors, which constitute part of the spliceosome. It interacts with other spliceosomal components bound to both the 5- and 3-splice sites during spliceosome assembly. SRSF2 mutations typically occur as missense mutations at Pro95. SRSF2 mutations have been reported in approximately 40% of cases of chronic myelomonocytic leukemia, but they may not have prognostic significance in that entity. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. In addition, SRSF2 mutations have been reported in approximately 15-20% of cases of myelodysplastic syndrome. SRSF2 mutations have also been described in 5-20% of patients with acute myeloid leukemia and appear to be enriched among AML patients with reduced blast counts. SRSF2 has been found to be mutated in approximately 10% of cases of primary myelofibrosis where mutations may occur together with mutations in JAK2, MPL, TET2, CBL, ASXL1, EZH2, IDH1/2. SRSF2 mutations are also present in 8% of blastic plasmacytoid dendritic cell neoplasm and 3% of polythemia vera. SRSF2 mutations tend to be (although are not entirely) exclusive of mutations in other splicing factor components. SRSF2 mutations are associated with a poor prognosis in myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic Syndromes), primary myelofibrosis, polycythemia vera, and KIT D816V-mutated advanced systemic mastocytosis. SRSF2 mutations are also reported to be highly specific for secondary acute myeloid leukemia, and may also be helpful in identifying a subset of elderly patients with de novo acute myeloid leukemia and therapy-related AML with worse clinical outcomes.

Last updated: 2018-11-12 20:40:58 UTC
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Tier 1
SETBP1
Variants
SETBP1 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Atypical Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

SETBP1 encodes a protein which is believed to inhibit PP2A phosphatase activity through SET stabilization. In addition, SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of a network of development genes through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex. Heterozygous, somatic, missense mutations are predominantly hot-spot mutations within the SKI homologous region in exon 4, which result in the functional loss of the degron motif responsible for the short half-life of the protein. Therefore, these mutations result in an increased half-life and accumulation of the mutated SETBP1, and thus increased inhibition of the oncosupressor PP2A through the SETBP1-SET-PP2A axis. In addition, mutations in SETBP1 potentially deregulate gene transcription mediated by SETBP1. SETBP1 mutations have been described in approximately 25% of atypical chronic myelogenous leukemia, 30% of juvenile myelomonocytic leukemia, 17% of secondary acute myeloid leukemia, 13% of myeloproliferative/myelodysplastic syndrome with ring sideroblasts and thrombocytosis, and 5-15% of chronic myelomonocytic leukemia. SETPB1 mutations appear to be rare (< 5%) or absent among cases of primary acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes, myeloproliferative neoplasms and chronic lymphocytic leukemia. SETBP1 mutations may be seen together with mutations in other genes such as ASXL1. Mutated SETBP1 provides supportive evidence for the diagnosis of atypical chronic myeloid leukemia, BCR-ABL1-negative in the 2016 revision of the WHO classification.SETBP1 mutations are associated with disease progression in myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic Syndromes), and unfavorable prognosis in chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, and MDS/MPN with ring sideroblasts associated and thrombocytosis.

Last updated: 2019-08-28 14:54:01 UTC
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Tier 1
JAK3
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
T Cell Lymphoproliferative Disorder
NK Cell Lymphoproliferative Disorder
T Lymphoblastic Leukemia/Lymphoma
Interpretation

JAK3 is a member of the Janus family of tyrosine kinases, which are involved in cytokine receptor-mediated signaling through the JAK/STAT pathway. JAK3 is believed to be essential for the development of lymphoid cells, especially mature T-cells and NK cells. Missense mutations of JAK3 have been described in approximately 34% of T cell prolymphocytic leukemias, 20% of natural killer cell lymphoma, 10% of T cell acute lymphoblastic leukemia including early T cell precursor T cell ALL and occasional cases of Down syndrome associated -myeloid leukemia, -transient leukemia and -acute megakaryoblastic leukemia. In addition, subclonal, secondary mutations of JAK3 have been reported in approximately 10% of juvenile myelomonocytic leukemia and may occur together with mutations the RAS pathway genes. Mutations of JAK3 are typically activating (gain of function) mutations and are potential therapeutic targets in some settings.

Last updated: 2016-06-05 02:09:42 UTC
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Tier 2
MEF2B
Variants
Primary Sites
Blood
Bone Marrow
Lymph Node
Tumor Types
Mantle Cell Lymphoma
Diffuse Large B Cell Lymphoma
Follicular Lymphoma
Interpretation

MEF2B is a calcium-regulated transcription factor that recruits histone-modifying enzymes. Missense and truncating MEF2B mutations have been reported in the MADS box and MEF2B domains in up to 5% of cases of mantle cell lymphoma, and up to 20% of diffuse large B cell lymphoma and follicular lymphoma.

Last updated: 2016-06-05 02:11:08 UTC
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Tier 1
CEBPA
Variants
CEBPA any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

Mutations of the transcription factor CEBPA (CCAAT/enhancer binding protein alpha) have been reported in approximately 15% of patients with acute myeloid leukemia (AML) with a normal karyotype. CEBPA plays a role in the differentiation of granulocytes. Two types of mutations have been reported: N-terminal changes which result in a truncated dominant negative isoform lacking one of the N terminal domain transactivation domains and C-terminal mutations which are in-frame insertions or deletions affecting the leucine zipper and preventing dimerization and DNA binding. Patients may carry both N- and C-terminal mutations affecting different alleles. Isolated, biallelic ("double") mutations (not single mutation) of CEBPA appear to be associated with a favorable-risk group of normal karyotype AML. CEBPA mutations have also been reported in association with hereditary myeloid disorders; 5-10% of CEBPA double mutant AML cases may harbor germline mutations. Recommend correlation with clinical findings including family history and genetic counseling, if there is clinical suspicion of an inherited disorder.

Last updated: 2019-08-28 14:54:01 UTC
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Tier 2
CNOT3
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
T Lymphoblastic Leukemia/Lymphoma
Interpretation

CNOT3 is part of the CCR4-NOT complex that regulates gene expression and may act as a tumor suppressor. CNOT3 is mutated in approximately 8% of adult T cell acute lymphoblastic leukemia cases.

Last updated: 2016-06-05 02:12:53 UTC
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Tier 2
U2AF2
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Interpretation

U2AF2 (U2AF65) is a member of the RNA splicing machinery and has been be reported to show missense mutations in less than 1% of cases of myelodysplastic syndromes and approximately 1% of cases of chronic myelomonocytic leukemia.

Last updated: 2016-06-05 02:13:42 UTC
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Tier 1
ASXL1
Variants
ASXL1 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Chronic Myelomonocytic Leukemia
Myelodysplastic Syndrome
Acute Myeloid Leukemia
Primary Myelofibrosis
Mast Cell Neoplasm
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

ASXL1 regulates epigenetic functions including histone and chromatin modifications. ASXL1 mutations have been reported in 40-50% of chronic myelomonocytic leukemia(CMML), 20% of myelodsyplastic syndromes, 20-35% of primary myelofibrosis, 15% of systemic mastocytosis, 30% of patients with secondary acute myeloid leukemia and 5-10% of primary acute myeloid leukemia. ASXL1 mutations have also been described in CHIP and CCUS. In CMML, missense mutations of ASXL1 appear to be less common (less than 10% of cases). Nonsense and frameshift mutations (but apparently not missense mutations) of ASXL1 have been reported to carry an adverse prognostic impact in cases of chronic myelomonocytic leukemia. In addition, ASXL1 mutations have been associated with adverse outcome in myelodysplasia, primary myelofibrosis and systemic mastocytosis. Among cases of AML, ASXL1 mutations appear to be associated with adverse prognosis in some subtypes of AML according to some, but not all, studies. ASXL1 mutations may coexist with mutations of splicing factor components, TET2 and RUNX1; for example, co-existence of U2AF1 and ASXL1 mutations have been described in CMML and primary myelofibrosis; While in AML, ASXL1 mutations have been reported to be exclusive of NPM1 mutations according to some studies.

Last updated: 2019-08-28 14:54:01 UTC
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Tier 1
GNAS
Variants
GNAS codon(s) 201, 844 any
Primary Sites
Blood
Bone Marrow
Tumor Types
Myelodysplastic Syndrome
Interpretation

GNAS (Guanine Nucleotide Binding Protein, Alpha, Stimulating Activity Polypeptide, G-S-alpha) is a component of the heterotrimeric G protein complex that has been shown to be mutated in less than 1% of myelodysplastic syndrome. Mutations of Arg201 of GNAS are typically activating mutations which have been described in various types of solid tumors and McCune Albright syndrome.

Last updated: 2016-06-05 02:16:46 UTC
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Tier 1
RUNX1
Variants
RUNX1 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Myelodysplastic Syndrome
Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
T Lymphoblastic Leukemia/Lymphoma
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

RUNX1(AML1, CBFA2) encodes the alpha subunit of core binding factor and is a transcription factor important in normal hematopoietic development. RUNX1 mutations have been reported in approximately 10% of myelodysplastic cases, 5-15% of acute myeloid leukemia, 8-37% of chronic myelomonocytic leukemia, 10% of T cell acute lymphoblastic leukemia, 3% of systemic mastocytosis, 2% of essential thrombocythemia and 2% of polycythemia vera. The mutations include frameshift, missense, nonsense, and splice site mutations. Typically, the Runt domain and the region just downstream of the Runt domain are affected and the mutations tend to be monoallelic. AML with RUNX1 mutation which does not fulfill the diagnostic criteria for other specific AML subtypes in the categories of AML with recurrent genetic abnormalities, therapy-related myeloid neoplasms, or AML with myelodysplasia-related changes is now classified the provisional entity of AML with mutated RUNX1. RUNX1 mutations may be associated with Trisomy 8 or MLL-PTD in AML according to some studies. They tend not to occur in AML cases with favorable cytogenetic findings and appear to be exclusive of NPM1 or CEBPA mutations in AML. Myeloid neoplasms, predominantly MDS/AML, developing in patients, usually at a young age, with a familial platelet disorder and germline monoallelic RUNX1 mutations are categorized as myeloid neoplasms with germline RUNX1 mutation. Of note, RUNX1 may also be involved in large intragenic deletions and translocations (e.g., t(8;21)(RUNX1-ETO), t(3;21)(RUNX1-EVI1), t(12;21)(TEL-RUNX1) which are not detected by this assay. Mutated RUNX1 is a poor-risk prognostic marker in AML unless it co-occurs with favorable-risk AML subtypes (NCCN Guidelines for AML). RUNX1 nonsense or frameshift mutations are associated with an unfavorable prognosis in myelodysplastic syndrome, independent of IPSS, IPSS-R, age, and other gene mutations (NCCN Guidelines for Myelodysplastic Syndromes). RUNX1 mutations are independently associated with unfavorable outcomes and shorter survival after hematopoietic stem cell transplantation in patients with myelodysplastic syndrome and myelodysplastic syndrome/acute myeloid leukemia. RUNX1 mutations are also associated with an unfavorable prognosis chronic myelomonocytic leukemia and systemic mastocytosis.

Last updated: 2019-08-28 14:54:01 UTC
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Tier 1
U2AF1
Variants
U2AF1 codon(s) 34 missense
U2AF1 codon(s) 157 missense
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Acute Myeloid Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

U2AF1 encodes for the small subunit of the U2 auxiliary factor, which is a non-small nuclear ribonucleoprotein (non-snRNP) required for the binding of U2 snRNP to the pre-mRNA branch site and plays critical role in RNA splicing. U2AF1 is one of several spliceosome complex genes frequently mutated in a variety of hematologic malignancies. Two hotspot mutations (S34 in exon 2 and Q157 in exon 6) occur within the two zinc-finger domains of the U2AF1 protein. These mutations have been reported in approximately 4- 9% of chronic myelomonocytic leukemia, 8-11% of cases of myelodysplastic syndrome (typically without ring sideroblasts), 16% of primary myelofibrosis, 12% of blastic plasmacytoid dendritic cell neoplasm, 4% of acute myeloid leukemia and 1% of essential thrombocythemia. U2AF1 mutations are associated with an unfavorable prognosis in myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic Syndromes) and essential thrombocythemia, and decreased response to lenalidomide in myeloid neoplasms with and without del(5q). U2AF1 mutations are also reported to be highly specific for secondary acute myeloid leukemia, and may also be helpful in identifying a subset of therapy-related AML or elderly de novo AML with worse clinical outcomes. U2AF1 mutations have been associated with altered splicing patterns in vitro and in vivo, and may play a significant role in the pathogenesis of myeloid malignancies due to selective mis-splicing of tumor-associated genes.

Last updated: 2018-11-12 20:41:11 UTC
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Tier 2
SF3A1
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Chronic Myelomonocytic Leukemia
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Interpretation

SF3A1 is a component of the RNA splicing machinery. Missense mutations of SF3A1 are rare in myelodsyplasia, chronic myelomonocytic leukemia and acute myeloid leukemia (less than 2% of cases).

Last updated: 2016-06-05 02:22:15 UTC
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Tier 2
EP300
Variants
EP300 any mutation
Primary Sites
Blood
Bone Marrow
Lymph Node
Tumor Types
T Lymphoblastic Leukemia/Lymphoma
Acute Leukemia of Unspecified Cell Type
Acute Myeloid Leukemia
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

EP300 is a histone acetyltransferase and transcriptional coactivator. Somatic mutations of EP300 have been described in cases of T cell acute lymphoblastic leukemia and other lymphoid malignancies including diffuse large B cell lymphoma and follicular lymphoma. Occasional splice site mutations have also been described which are not detected by this assay. EP300 mutations have also been described in the Rubinstein-Taybi developmental syndrome.

Last updated: 2019-08-28 14:54:02 UTC
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Tier 1
CRLF2
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
B Lymphoblastic Leukemia/Lymphoma
Interpretation

Cytokine receptor-like factor 2 (CRLF2) is a type I cytokine receptor subunit that dimerizes with IL7R to form the receptor for thymic stromal lymphopoietin (TSLP). Heterozygous, somatic, gain-of-function mutations introducing cysteines in the transmembrane domain have been described in up to 20% of B cell acute lymphoblastic leukemias (ALL). These mutations cause ligand independent dimerization via disulfide bonds. The disulfide bond is critical for the activation since elimination of the cysteines abrogated the cytokine independent growth. In addition, more recently, another activating, non-cysteine mutation in the heterodimerization domain of CRLF2 has been reported.

Last updated: 2016-06-05 02:24:17 UTC
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Tier 1
ZRSR2
Variants
ZRSR2 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

ZRSR2 endoes a component of the RNA splicing machinery which associates with the U2 auxillary factor and is involved in the recognition of the 3'-splice site during the stages of spliceosome assembly. Mutations in ZRSR2 have been reported in approximately 3-11% of myelodysplasia, 4-8% of chronic myelomonocytic leukemia, 8% of blastic plasmacytoid dendritic cell neoplasm and less than 5% of acute myeloid leukemia and myeloproliferative neoplasms. Unlike other spliceosomal genes, ZRSR2 mutations do not occur in select "hot spots". Nearly all reported mutations are nonsense or frameshift mutations, compatible with loss-of-function mutations and suggesting a tumor suppressor role of ZRSR2. ZRSR2 mutations tend to be exclusive of mutations in most other components of the RNA splicing machinery. Aberrant splicing of U12-type introns has been shown to be a hallmark feature of MDS with ZRSR2 mutations. ZRSR2 mutations are associated with an unfavorable prognosis in myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic Syndromes). ZRSR2 mutations are also reported to be highly specific for secondary acute myeloid leukemia, and may also be helpful in identifying a subset of therapy-related AML and elderly de novo AML with worse clinical outcomes.

Last updated: 2019-08-28 14:54:02 UTC
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Tier 1
BCOR
Variants
BCOR any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Chronic Myelomonocytic Leukemia
Myelodysplastic Syndrome
Acute Myeloid Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

BCOR is a ubiquitously expressed nuclear protein that is a transcriptional corepressor important in several cellular processes. Somatic, nonsense and frameshift mutations throughout BCOR have been reported in approximately 7% of chronic myelomonocytic leukemia, 4% of patients with myelodysplastic syndrome(MDS), 4% of primary acute myeloid leukemia and appear to be associated with RUNX1 and DNMT3A mutations . Also, BCOR mutations may be enriched among cases of AML lacking NPM1, CEBPA, FLT3-ITD, IDH1 and MLL-PTD alterations. BCOR mutations tend to be subclonal in MDS, clonal in primary AML and are believed to have significance as loss of function mutations in a tumor suppressor gene that affect the functional allele in male and female patients. The presence of BCOR mutation in patients with MDS and AML has been associated with poorer overall survival according to some studies.

Last updated: 2019-08-28 14:54:02 UTC
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Tier 2
GATA1
Variants
GATA1 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

The GATA1 transcription factor is important in the development of erythroid and megakaryocytic lineages. Amino-terminal, small insertion/deletion(frameshift), nonsense and missense mutations of GATA1 have been described in almost all patients with transient abnormal myelopoiesis(TAM) and acute megakaryoblastic leukemia associated with Down syndrome (Trisomy 21)(DS-AMKL). Studies suggest that the cases of TAM which progress to DS-AMKL are associated with the acquisition of additional driver mutations in other genes including the cohesin complex genes as well as CTCF and EZH2. The amino-terminal GATA1 mutations lead to a lack of the N-terminal amino acids and translation from an alternate start codon (methionine at position 84 in exon 3). GATA1 mutations appear to be rare in acute megakaryoblastic leukemia not associated with Down syndrome. GATA1 mutations have also been reported in the context of hereditary myeloid disorders. If clinical findings and family history are concerning for an inherited disorder, then genetic counseling may be helpful, if clinically indicated.

Last updated: 2019-08-28 14:54:02 UTC
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Tier 2
SMC1A
Variants
SMC1A any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Chronic Myeloid Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

SMC1A belongs to the cohesin complex family of genes that encode protein subunits of the cohesion complex, which regulates chromosomal segregation. SMC1A has been reported to show somatic, missense mutations throughout the gene in less than 5% of cases of acute myeloid leukemia and less than 5% of chronic myeloid leukemia. Mutations of SMC1A are mostly mutually exclusive of mutations in other components of the cohesin complex. Mutations of SMC1A may be enriched in male patients since the gene is located on the X chromosome. Cohesin complex mutations are associated with an unfavorable prognosis in myelodysplastic syndrome, and are more frequently found in patients with high IPSS scores and secondary acute myeloid leukemia.

Last updated: 2019-08-28 14:54:02 UTC
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Tier 1
STAG2
Variants
STAG2 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Chronic Myelomonocytic Leukemia
Myelodysplastic Syndrome
Acute Myeloid Leukemia
Chronic Myeloid Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

STAG2 belongs to the cohesin complex family of genes that encode protein subunits of the cohesion complex, which regulates chromosomal segregation. STAG2 has been reported to show somatic, nonsense, frameshift and occasional missense mutations throughout the gene in 6% of cases of myelodysplasia, 10% of chronic myelomonocytic leukemia, 6% of cases of acute myeloid leukemia, and less than 5% of chronic myeloid leukemia and myeloproliferative neoplasms. Mutations of STAG2 are mostly mutually exclusive of mutations in other components of the cohesin complex. STAG2 mutation is associated with a poor prognosis in myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic syndromes). STAG2 mutations are also reported to be highly specific for secondary acute myeloid leukemia, and may also be helpful in identifying a subset of elderly patients with de novo acute myeloid leukemia or therapy-related AML with worse clinical outcomes.

Last updated: 2019-08-28 14:54:02 UTC
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Tier 2
BCORL1
Variants
BCORL1 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Interpretation

BCORL1 is a transcriptional corepressor and putative tumor suppressor gene. Somatic, nonsense and frameshift mutations have been reported throughout BCORL1 in 6% of acute myeloid leukemia, 10% of patients with acute myeloid with myelodysplasia related changes, less than 1% of myelodysplasia and less than 2% of chronic myelomonocytic leukemia. BCORL1 is located on the X-chromosome.

Last updated: 2018-11-12 20:40:43 UTC
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Tier 2
PHF6
Variants
PHF6 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
T Lymphoblastic Leukemia/Lymphoma
Acute Myeloid Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

PHF6 encodes a member of the plant homeodomain (PHD)-like finger (PHF) family with two PHD-type zinc finger domains, indicating a potential role in transcriptional regulation. It is localized to the nucleolus and may play a role in recognizing methylation status of histone lysines. Somatic, nonsense, frameshift and occasional missense mutations throughout PHF6 have been reported in up to 38% of cases of T cell acute lymphoblastic leukemia. In T-ALL, PHF6 mutations often co-exist with NOTCH1 mutations. PHF6 mutations have also been reported in approximately 3% of cases of acute myeloid leukemia, less than 5% of chronic myeloid leukemia in blast phase, and 3% of myelodysplastic syndrome. In acute myeloid leukemia, PHF6 mutations have been associated with male preponderance and reduced overall survival in patients with normal karyotype or intermediate-rish cytogenteics abnormalities. Mutated PHF6 is more frequent in MDS cases with excess blasts, but there appears to be no association with survival (NCCN Guidelines for Myelodysplastic Syndromes). PHF6 mutation status does not appear to affect outcome in T-ALL according to some studies.

Last updated: 2019-08-28 14:54:02 UTC
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Tier 1
RPL10
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
T Lymphoblastic Leukemia/Lymphoma
Interpretation

RPL10 is a ribosomal protein of the 60S ribosomal subunit and shows missense mutations in approximately 5-8% of pediatric patients with T-cell acute lymphoblastic leukemia. The most common mutation is at p.Arg98. Functional studies suggest that the p.Arg98Ser mutation of RPL10 is associated with a ribosomal biogenesis defect. RPL10 is located on the X chromosome and RPL10 mutations may be enriched in male patients.

Last updated: 2016-06-05 02:33:51 UTC
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Tier 2
BRCC3
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Myelodysplastic Syndrome
Interpretation

BRCC3 is a component of the DNA repair pathway. Nonsense and missense mutations have been reported in less than 5% of myelodysplasia.

Last updated: 2016-06-05 02:34:55 UTC
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Tier 1
CALR
Variants
CALR exon(s) 9 frameshift
Primary Sites
Blood
Bone Marrow
Tumor Types
Myeloproliferative Neoplasm
Essential Thrombocythemia
Primary Myelofibrosis
MDS with Ring Sideroblasts
Myelodysplastic Syndrome
Acute Leukemia of Unspecified Cell Type
Acute Myeloid Leukemia
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

Calreticulin(CALR) is an endoplasmic reticulum chaperone protein. Somatic insertions and deletions in exon 9 of calreticulin that cause a +1bp frameshift and a novel carboxy-terminal peptide in mutant calreticulin have been reported in 70% of JAK2/MPL-negative essential thrombocythemia (ET)and 56-88% of JAK2/MPL-negative primary myelofibrosis(PMF). In addition, CALR mutations have been reported in approximately 10% of patients with myelodysplasia, including JAK2/MPL-negative refractory anemia with ring sideroblasts (RARS-T) where it may co-occur with mutations in SF3B1. In ET, PMF, and RARS-T, calreticulin mutations appear to be mutually exclusive of mutations in JAK2 or MPL. The CALR mutations lead to loss of the endoplasmic reticulum retention motif (KDEL) sequence in the carboxy-terminal portion of mutant CALR. Calreticulin mutations appear to be absent in polycythemia vera, acute myeloid leukemia, chronic myeloid leukemia, systemic mastocytosis, lymphoid malignancies and are rare in atypical chronic myeloid leukemia and chronic myelomonocytic leukemia. The most common 52bp deletion mutation (Type 1) in CALR has been shown to lead to cytokine-independent growth and activation of STAT5. Type 2 (5 bp insertion) mutations have also been described. This represents a potentially targettable pathway alteration. Patients with some types of mutant CALR may show improved survival and lower risk of thrombosis compared to patients with mutant JAK2, according to some, but not all studies.

Last updated: 2018-11-12 20:41:00 UTC
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Tier 1
MAP2K1
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Hairy Cell Leukemia
Interpretation

MAP2K1(MEK1) is a kinase which is downstream of BRAF and upstream of ERK-1/-2 in the MAPK pathway. MAP2K1 missense mutations and small in frame deletions have been reported in approximately 50% of hairy cell leukemia-variant (HCL-variant) cases, regardless of IGHV4-34–status, and greater than 50% of cases of IGHV4-34–positive classic hairy cell leukemia (classic HCL). These mutations are predicted to increase the basal enzymatic activity. MAP2K1 mutations appear to be mutually exclusive of the BRAF p.Val600Glu mutation, which appears to be largely specific to IGHV4-34–negative, classic HCL. Nevertheless, MAP2K1 mutations have been described as a mechanism of resistance to targetted therapy with BRAF inhibitors. The MAPK pathway alterations are potentially targetable.

Last updated: 2016-06-05 02:39:09 UTC
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Tier 1
PIGA
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Interpretation

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hemolytic disorder that shows intravascular hemolysis and hemoglobinuria. Other clinical findings include thrombocytopenia and/or leukocytopenia and recurrent venous thrombosis. PNH results from the expansion of an abnormal clone of hematopoietic stem cells harboring somatic mutation in phosphotidylinositol glycan complementation class A (PIGA) gene, which appears to have a survival advantage. The PIGA gene maps to Xp22.1; therefore only one allele of PIGA is transcribed in both sexes because of X inactivation. Pathogenic mutation results in a deficiency in the surface expression of all GPI-anchored proteins (GPI-AP) because of defective synthesis of glycosylphosphatidylinositol (GPI). In all reported cases of acquired PNH, the mutation is detected only in the PIGA gene. PIGA germline mutations have been described in Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 2 . Pathogenic mutations in PIGA tend to be nonsense, frameshift and occasionally splice site and missense mutations occurring throughout the gene. Detection of PNH clones by flow cytometry is done by studying the expression of GPI-AP on RBC and PB leukocytes using monoclonal antibodies specific for these proteins or by studying the GPI anchor itself, using FLAER. Correlation with other clinical and lab findings as well as family history is recommended. Genetic counseling may be helpful, if clinically indicated.

Last updated: 2016-06-07 01:43:40 UTC
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Tier 2
EGFR
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Interpretation

Despite pre-clinical data and case reports of response to EGFR inhibitors, the EGFR inhibitor gefitinib does not appear to be effective in the treatment of advanced AML .

Last updated: 2016-06-05 02:44:56 UTC
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Tier 1
GNB1
Variants
GNB1 codon(s) 57 missense
Primary Sites
Blood
Bone Marrow
Tumor Types
Myelodysplastic Syndrome
Acute Myeloid Leukemia
Interpretation

Guanine nucleotide binding protein (G protein), beta polypeptide 1(GNB1) encodes a beta subunit of heterotrimeric G-proteins. Recurrent missense mutations at the Lys57 codon of GNB1 (eg, p.K57E, p.K57N, p.K57T) in the WD40 repeat motif have been reported in less than 5 % of myelodysplasia/secondary acute myeloid leukemia and de novo AML. The lysine at codon 57 of GNB1 has been reported to interact with the G-protein subunit alpha(GNAS), which itself has also been shown to be recurrently mutated in myelodysplasia. According to some studies, Lys57Ala mutations lead to altered downstream signaling in some G-protein coupled receptor signaling pathways. Overall, these findings suggests that mutations at Lys57 of GNB1 are pathogenic. In addition, frameshift mutation at codon 53 of GNB1 has also been described in myelodysplasia.

Last updated: 2016-06-05 02:47:45 UTC
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Tier 2
AKT1
Variants
AKT1 E17K
Primary Sites
Breast
Endometrium
Prostate
Lung
Ovary
Colon
Rectum
Tumor Types
Adenocarcinoma
Carcinoma
Interpretation

AKT1 mutations have been reported in a variety of tumor types such as endometrial, lung, breast, colorectal, ovarian, and prostate cancers. The mutations are mutually exclusive from PIK3CA mutations. Increased expression and activation of AKT1 observed in many cancers is caused by a variety of different mechanisms including genomic alterations of AKT1, PIK3CA, PTEN, RAS family members, or growth factor receptors. Gain-of-function alterations of AKT1 can lead to neoplastic transformation in model systems, and is a potential target for therapeutic strategies. The E17K variant is by far the most frequent AKT1 mutation reported, implicating it as an important tumor promoting event.

Last updated: 2016-10-11 21:31:48 UTC
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Tier 2
APC
Variants
APC any missense
APC any nonsense
APC any frameshift
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

Somatic APC mutations are common events in colorectal adenocarcinomas, reported in up to 76% of the cases. Loss of normal APC function is known to be an early event in both familial and sporadic colon cancer pathogenesis, occurring at the pre-adenoma stage. APC mutations do not appear to significantly affect the prognosis of colorectal cancer patients. While there are a number of small molecule inhibitors in development that target the Wnt pathway, there is currently no matched targeted therapy available for colorectal cancer patients harboring an APC mutation.

Last updated: 2017-03-15 21:09:57 UTC
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Tier 2
APC
Variants
APC codon(s) 1464 frameshift
APC Q1338*
APC R1114*
APC codon(s) 1556 frameshift
APC R876*
APC codon(s) 1465 frameshift
APC codon(s) 1307 frameshift
APC Q1429*
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

Somatic APC mutations are common events in colorectal adenocarcinomas, reported in up to 76% of the cases. Loss of normal APC function is known to be an early event in both familial and sporadic colon cancer pathogenesis, occurring at the pre-adenoma stage. APC mutations do not significantly affect the prognosis of colorectal cancer patients. While there are a number of small molecule inhibitors in development that target the Wnt pathway, there is currently no matched targeted therapy available for colorectal cancer patients harboring an APC mutation.

Last updated: 2017-03-15 21:14:46 UTC
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Tier 3
APC
Variants
APC E1317Q
Primary Sites
Colon
Stomach
Thyroid
Rectum
Tumor Types
Adenocarcinoma
Carcinoma
Interpretation

Familial adenomatous polyposis (FAP) is a disease with autosomal-dominant inheritance that predisposes to carcinoma of the colorectum, stomach, duodenum, and thyroid. There is increasing evidence that germline variants in APC (E1317Q) predispose to the development of multiple colorectal adenomas and carcinoma.

Last updated: 2015-12-09 20:11:10 UTC
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Tier 3
APC
Variants
APC E1317Q
APC codon(s) 1307 frameshift
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Interpretation

Germline APC mutations are characteristically associated with Familial Adenomatous Polyposis (FAP) that predisposes to carcinomas of the colo-rectum, stomach, duodenum, and thyroid. Recently somatic mutations in exon 15 of APC gene have been described in certain sporadic papillary thyroid carcinomas. The prognostic impact of these mutations remains unknown in such settings.

Last updated: 2017-08-24 22:00:52 UTC
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Tier 3
APC
Variants
APC E1317Q
APC codon(s) 1307 frameshift
Primary Sites
Lung
Tumor Types
Squamous Cell Carcinoma
Adenocarcinoma
Interpretation

APC mutations have been reported in lung squamous cell carcinoma and small-cell lung carcinoma, but rarely in lung adenocarcinoma. However, variants in the APC gene have not been well characterized in lung adenocarcinoma and their clinical significance is unclear. According to ClinVar, this particular variant is a likely benign germline variant (https://preview.ncbi.nlm.nih.gov/clinvar/variation/829/).

Last updated: 2019-02-22 18:05:35 UTC
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Tier 3
ATM
Variants
ATM P604S
ATM A1309T
ATM F858L
ATM P2699S
Primary Sites
Lung
Breast
Colon
Rectum
Unknown
Esophagus
Stomach
Tumor Types
Adenocarcinoma
Interpretation

ATM alterations have been reported as germline variants which predispose to inherited cancer syndromes and as somatic (acquired) variants in tumors. ATM is part of many signalling networks, including cell metabolism and growth, oxidative stress, and chromatin remodelling, all of which can affect cancer progression. Although ATM is considered to be a tumour suppressor, ATM signaling may be advantageous to cancer cells in some settings, particularly in resistance to radio- and chemotherapeutic treatment. For this reason, the use of ATM inhibitors in cancer therapy is under exploration.

Last updated: 2019-01-22 18:50:49 UTC
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Tier 3
ATM
Variants
ATM P604S
ATM A1309T
ATM F858L
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Interpretation

ATM alterations have been reported as germline variants which predispose to inherited cancer syndromes and as somatic (acquired) variants in tumors. ATM is part of many signalling networks, including cell metabolism and growth, oxidative stress, and chromatin remodelling, all of which can affect cancer progression. Although ATM is rightly considered to be a tumour suppressor, ATM signalling can also be advantageous to cancer cells, particularly in resistance to radio- and chemotherapeutic treatment. For this reason, ATM inhibitors have been developed for use in cancer therapy.

Last updated: 2016-06-07 01:52:16 UTC
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Tier 3
ATM
Variants
ATM P604S
ATM A1309T
ATM F858L
Primary Sites
Skin
Breast
Tumor Types
Melanoma
Interpretation

ATM alterations have been reported as germline variants which predispose to inherited cancer syndromes and as somatic (acquired) variants in tumors, including breast cancer. ATM is part of many signalling networks, including cell metabolism and growth, oxidative stress, and chromatin remodelling, all of which can affect cancer progression. Although ATM is rightly considered to be a tumour suppressor, ATM signalling can also be advantageous to cancer cells, particularly in resistance to radio- and chemotherapeutic treatment. For this reason, ATM inhibitors have been developed for use in cancer therapy.

Last updated: 2016-06-07 01:48:50 UTC
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Tier 1
BRAF
Variants
BRAF V600E
BRAF codon(s) 600 any
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Interpretation

Eighty percent of all thyroid cancers are papillary thyroid carcinomas (PTCs). BRAF is part of the mitogen-activated protein kinase (MAPK) signaling pathway and V600E is an activating mutation of BRAF. The BRAF V600E mutation has been reported in 45% of patients with papillary thyroid carcinoma. The BRAF V600E-like PTC's (BVL) and the RAS-like PTC (RL-PTC) are fundamentally different in their genomic, epigenomic, and proteomic profiles. Presence of a BRAF p.Val600Glu (V600E) mutation is highly specific for papillary thyroid carcinoma and is only rarely associated with the follicular variant PTC , other well-differentiated thyroid neoplasms or nodular goiters. The possible prognostic impact of BRAF V600E mutations in papillary carcinoma of the thyroid continues to be studied. FDA approved dabrafenib and trametinib administered together for the treatment of BRAF V600E mutation-positive anaplastic thyroid cancer.

Last updated: 2019-04-05 17:25:22 UTC
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Tier 1
BRAF
Variants
BRAF V600E
BRAF codon(s) 600 any
BRAF V600D
BRAF V600K
BRAF V600R
BRAF V600M
BRAF V600G
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

Presence of a BRAF c.1799T>A, p.Val600Glu (V600E) mutation in a microsatellite unstable colorectal carcinoma indicates that the tumor is probably sporadic and not associated with Lynch syndrome (HNPCC). However, if a BRAF mutation is not detected, the tumor may either be sporadic or Lynch syndrome associated. Detection of BRAF mutations may also be useful in determining patient eligibility for anti-EGFR treatment. Approximately 8--15% of colorectal cancer (CRC) tumors harbor BRAF mutations. The presence of BRAF mutation is significantly associated with right-sided colon cancers and is associated with decreased overall survival. Some studies have reported that patients with metastatic CRC (mCRC) that harbor BRAF mutations do not respond to anti-EGFR antibody agents cetuximab or panitumumab in the chemotherapy-refractory setting. BRAF V600-mutated CRCs may not be sensitive to V600E targeted TKIs. Drug: Vemurafenib + Panitumumab, Encorafenib + Binimetinib + Cetuximab, Radiation + Trametinib + Fluorouracil

Last updated: 2018-03-15 21:07:15 UTC
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Tier 1
BRAF
Variants
BRAF V600E
BRAF codon(s) 600 any
BRAF V600D
BRAF V600K
BRAF V600R
BRAF V600M
BRAF V600G
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. BRAF mutations are present in approximately 50% to 60% of cutaneous melanomas and are also present at lower frequencies in other melanoma subtypes. The hotspot for mutations in BRAF is at codon Val600 and the most common one is p.Val600Glu (V600E). Various B-Raf inhibitors(Vemurafenib, Dabrafenib) have been FDA approved for melanoma therapy in certain settings. Drug: Vemurafenib Dabrafenib Dabrafenib + Trametinib Vemurafenib + Cobimetinib Trametinib

Last updated: 2018-03-15 21:12:31 UTC
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Tier 2
BRAF
Variants
BRAF V600D
BRAF V600K
BRAF V600R
BRAF V600M
BRAF V600G
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations in BRAF have been found in 1-4% of all NSCLC most of which are adenocarcinomas and may be a potential therapeutic target in some settings. Drug: Vemurafenib, Dabrafenib, Dabrafenib + Trametinib

Last updated: 2018-06-13 18:59:16 UTC
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Tier 2
BRAF
Variants
BRAF G469A
BRAF codon(s) 469 any
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations in BRAF have been found in 1-4% of all NSCLC most of which are adenocarcinomas. The G469A mutation results in an amino acid substitution at position 469 in BRAF, occurs within the highly conserved motif of the kinase domain. Most mutant BRAF proteins, such as G469A, have increased kinase activity and are transforming in vitro. In preclinical studies, lung cancer cell lines harboring the BRAF G469A mutation were not sensitive to dasatinib

Last updated: 2020-07-24 14:51:34 UTC
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Tier 2
BRAF
Variants
BRAF G464V
BRAF codon(s) 464 any
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations in BRAF have been found in up to 10% of all NSCLC, more common in adenocarcinomas. The G464V mutation results in an amino acid substitution within the highly conserved motif of the kinase domain. This specific mutation is a low frequency cancer-associated variant classified as an intermediate activity mutant that moderately increases ERK activation and can transform cells. The predictive significance of this mutation needs further study. Clinical correlation is recommended.

Last updated: 2017-02-27 21:13:32 UTC
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Tier 2
BRAF
Variants
BRAF K601E
BRAF codon(s) 601 any
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations in BRAF have been found in 1-4% of all NSCLC most of which are adenocarcinomas. The K601E mutation results in an amino acid substitution at position 601 in BRAF, occurs within the highly conserved motif of the kinase domain. Most mutant BRAF proteins, such as K601E, have increased kinase activity and are transforming in vitro. Preclinical studies suggest that downstream signaling induced by the K601E mutant may be blocked by the BRAF inhibitor, vemurafenib.

Last updated: 2020-07-24 14:51:40 UTC
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Tier 2
BRAF
Variants
BRAF D594E
BRAF codon(s) 594 any
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

The D594E mutation in BRAF is believed to result in inactivation of BRAF and, therefore, BRAF inhibitors are not likely to be effective.

Last updated: 2017-03-15 21:02:32 UTC
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Tier 1
BRAF
Variants
BRAF V600E
BRAF codon(s) 600 any
Primary Sites
Spinal Cord
Brain
Brain, Supratentorial
Brain, Infratentorial
Tumor Types
Glioblastoma
Pleomorphic Xanthoastrocytoma
Ganglioglioma
Neuroepithelial Neoplasm, NOS
Neuroepithelial neoplasm, high grade
Astrocytoma, NOS
Astrocytoma, Pilocytic
Interpretation

BRAF alterations have been described in a wide spectrum of brain tumors, including in gliomas and glioneuronal tumors. BRAFV600E mutations have been found in approximately 10--15% of pilocytic astrocytoma and in approximately 5--10% of pediatric diffusely infiltrating gliomas, including diffuse astrocytomas (WHO grade II), anaplastic astrocytomas (WHO grade III) and glioblastomas (WHO grade IV), but in less than 2% of comparable adult gliomas. This mutation is potentially targetable.

Last updated: 2018-09-18 14:47:52 UTC
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Tier 2
BRAF
Variants
BRAF T599_V600insT
Primary Sites
Spinal Cord
Brain
Brain, Supratentorial
Brain, Infratentorial
Tumor Types
Interpretation

BRAF mutants, with a 3bp insertion between codons 599 and 600, display increased in vitro kinase activity activation potential comparable to those of BRAF V600E mutants.

Last updated: 2015-12-09 20:12:43 UTC
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Tier 3
CTNNB1
Variants
CTNNB1 codon(s) 32, 33, 34, 35, 36, 37, 41, 45 any
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

Somatic mutations in CTNNB1 (Beta-catenin) have been found in ~2-3% of malignant melanomas. Preclinical models have demonstrated that concurrent mutations in Beta-catenin and NRAS are synergistic in promoting melanoma formation.

Last updated: 2020-07-24 14:51:09 UTC
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Tier 2
CTNNB1
Variants
CTNNB1 S45P
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

CTNNB1 encodes the protein b-catenin, a transcriptional activator involved in the WNT signaling pathway. Somatic gain-of-function mutations in CTNNB1 result in aberrant accumulation of the b-catenin protein and are prevalent in a wide range of solid tumors, including endometrial carcinoma, ovarian carcinoma, hepatocellular carcinoma, and colorectal carcinoma, among others. Genetic alterations in CTNNB1 have been identified in 4% of non-small cell lung cancers. The CTNNB1 S45P mutation is likely oncogenic, but no real progress has been made in targeting oncogenic mutant forms of CTNNB1 in lung cancer. However, CTNNB1 mutation-positive cancers are presumed to be resistant to pharmacologic inhibition of upstream components of the WNT pathway, instead requiring direct inhibition of b-catenin function. In one study pharmacological inhibition of b-catenin suppressed EGFR-L858R/T790M mutated lung tumor and genetic deletion of the b-catenin gene dramatically reduced lung tumor formation in transgenic mice, suggesting that b-catenin plays an essential role in lung tumorigenesis and that targeting the b-catenin pathway may provide novel strategies to prevent lung cancer development or overcome resistance to EGFR TKIs. These results should be interpreted in the clinical context.

Last updated: 2019-01-22 18:31:14 UTC
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Tier 2
CTNNB1
Variants
CTNNB1 codon(s) 41, 45 any
Primary Sites
Chest Wall
Tumor Types
Fibromatosis
Interpretation

CTNNB1 mutations are highly prevalent and were detected in 84 to 87% of all sporadic fibromatosis/desmoid tumors. Most CTNNB1 mutations in fibromatosis/desmoid tumors are predominantly missense mutations in codons 41 and 45 of exon 3. These mutations result in β-catenin stabilization, increased nuclear accumulation and activation of the Wnt signaling pathway. Specific CTNNB1 mutations have been reported to predict recurrence in some cases of extra-abdominal and abdominal aggressive fibromatosis. A S45F mutation increased the risk of recurrence significantly.

Last updated: 2016-06-07 01:55:04 UTC
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Tier 2
CTNNB1
Variants
CTNNB1 S37Y
CTNNB1 codon(s) 32, 33, 34, 35, 36, 37, 41, 45 any
Primary Sites
Brain
Spinal Cord
Brain, Supratentorial
Brain, Infratentorial
Tumor Types
Craniopharyngioma
Interpretation

Mutations in beta catenin (CTNNB1) are seen in about 90% of adamantinomatous craniopharyngiomas and mutations in BRAF (V600E) in papillary craniopharyngiomas. Adamantinomatous and papillary craniopharyngiomas have been shown to carry clonal mutations that are mutually exclusive. These findings indicate that the adamantinomatous and papillary subtypes have distinct molecular underpinnings, each principally driven by mutations in a single well-established oncogene - CTNNB1 in the adamantinomatous form and BRAF in the papillary form, independent of age. This may have implications for the diagnosis and treatment of these tumors.

Last updated: 2020-07-24 14:51:45 UTC
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Tier 2
CDKN2A
Variants
CDKN2A W110*
CDKN2A Y129*
CDKN2A any frameshift
CDKN2A H83Y
CDKN2A codon(s) 58 frameshift
CDKN2A codon(s) 80 frameshift
CDKN2A D108H
Primary Sites
Lung
Tumor Types
Squamous Cell Carcinoma
Interpretation

Somatic mutations of CDKN2A are present in various tumor types, including, squamous cell carcinoma of the lung, clear cell sarcoma, head and neck cancer, melanoma and esophageal cancer. Majority of the CDKN2A mutations span exon 2 and result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. Multiple preclinical and clinical studies are ongoing for CDKN2A deficient tumors in multiple tumor types.

Last updated: 2018-06-13 19:01:26 UTC
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Tier 2
CDKN2A
Variants
CDKN2A W110*
CDKN2A any frameshift
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

Somatic mutations of CDKN2A are present in various tumor types, including, squamous cell carcinoma of the larynx, clear cell sarcoma, head and neck cancer, melanoma and esophageal cancer. Majority of the CDKN2A mutations span exon 2 and result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. Multiple preclinical and clinical studies are ongoing for CDKN2A deficient tumors in multiple tumor types.

Last updated: 2018-10-11 19:06:59 UTC
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Tier 3
CDKN2A
Variants
CDKN2A W110*
Primary Sites
Esophagus
Tumor Types
Carcinoma
Interpretation

Somatic mutations of CDKN2A are present in various tumor types, including, squamous cell carcinoma of the larynx, clear cell sarcoma, head and neck cancer, melanoma and esophageal cancer. Majority of the CDKN2A mutations span exon 2 and result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. Multiple preclinical and clinical studies are ongoing for CDKN2A deficient tumors in multiple tumor types.

Last updated: 2018-03-06 17:55:09 UTC
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Tier 2
CDKN2A
Variants
CDKN2A Y129*
CDKN2A W110*
CDKN2A any frameshift
CDKN2A codon(s) 58 frameshift
CDKN2A codon(s) 80 frameshift
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations of CDKN2A are present in various tumor types, including, squamous cell carcinoma of the larynx, clear cell sarcoma, head and neck cancer, melanoma and esophageal cancer, among other cancer types. Majority of the CDKN2A mutations span exon 2 and result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. Multiple preclinical and clinical studies are ongoing for CDKN2A deficient tumors in multiple tumor types.

Last updated: 2018-04-19 15:53:50 UTC
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Tier 2
ERBB2
Variants
ERBB2 G776delinsVC
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

ERBB2 (also HER2) is a transmembrane receptor that is a member of the ERBB family of receptor tyrosine kinases. ERBB2 is altered by amplification and/or overexpression in various cancers, most frequently in breast, esophagogastric and endometrial cancers. Somatic mutations in ERBB2 have been identified in a series of tumors including lobular breast, lung adenocarcinoma, and gastric cancers, among others, with recurrent hotspot alterations in both the extracellular and kinase domains. Preclinical and clinical studies have demonstrated that many of these mutations are transforming and sensitive to FDA-approved ERBB targeted therapies, including trastuzumab, ado-trastuzumab emtansine, lapatinib, and pertuzumab. The ERBB2 p.G776delinsVC variant is one of the in-frame insertions in exon 20 of ERBB2 that have been described in lung adenocarcinoma. Overall, in-frame ERRB2 insertions in exon 20 have been reported in approximately 6% of cases of lung adenocarcinoma which are negative for EGFR, KRAS, ALK alterations and these variants are more frequent in patients who were never-smokers. In vitro studies have shown that this specific variant is associated with constitutive kinase activation and is associated with sensitivity to some ERBB2 inhibitors and therefore, it may represent a targetable mutation in some clinical settings. Please refer to clinicaltrials.gov for additional information. Recommend correlation with other clinical and laboratory findings.

Last updated: 2019-01-22 18:40:47 UTC
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Tier 2
EGFR
Variants
EGFR A289V
EGFR A289D
EGFR G598V
EGFR P596L
EGFR codon(s) 289, 596, 598 any
Primary Sites
Spinal Cord
Brain
Brain, Supratentorial
Brain, Infratentorial
Tumor Types
Glioblastoma
Interpretation

EGFR mutations in GBM cluster in the extracellular (EC) domain and include in-frame deletions (such as the common “variant III” del 6-273) and missense mutations (A289V, A289D, T263P, G598V). In vitro and in vivo studies reveal anchorage-independent growth and tumorigenic potential when the A289 and G598 variants are stably expressed in NIH-3T3 cells. The A289 and G598 mutations sensitize Ba/F3 cells to erlotinib in vitro according to some reports, although other reports state glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). The A289 variant has been reported to show sensitivity towards BAY846, a tyrosine kinase inhibitor in brain tumors. In addition, according to some reports, inhibitors which bind to the inactive EGFR conformation potently inhibit EGFR EC mutants and induce cell death in EGFR mutant GBM cells.

Last updated: 2015-12-09 20:15:19 UTC
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Tier 1
EGFR
Variants
EGFR L858R
EGFR exon(s) 18, 19, 20, 21 any
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to EGFR inhibitors. Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions , EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M.

Last updated: 2021-10-19 15:34:57 UTC
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Tier 1
EGFR
Variants
EGFR E746_A750delinsI
EGFR exon(s) 19 deletion
EGFR E746_A750del
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions , EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. Erlotinib Afatinib Gefitinib Osimertinib

Last updated: 2018-04-06 14:53:53 UTC
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Tier 1
EGFR
Variants
EGFR codon(s) 790 any
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions , EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M.

Last updated: 2017-04-10 19:21:46 UTC
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Tier 3
EGFR
Variants
EGFR exon(s) 20 any
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

EGFR D770N in Exon 20 has been reported. The significance is unknown.

Last updated: 2015-12-09 20:15:45 UTC
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Tier 1
EGFR
Variants
EGFR exon(s) 20 insertion
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

EGFR exon 20 insertion testing identifies a distinct subset of lung adenocarcinomas, accounting for at least 9% of all EGFR-mutated cases and by molecular modeling, are predicted to have potentially different effects on erlotinib binding. Studies show that in contrast to the more classic activating EGFR mutations, these insertions have been associated with de novo resistance to approved EGFR-TKIs (erlotinib and gefitinib). In a recent study, patients with advanced lung adenocarcinoma harboring exon 20 insertions demonstrated no response or partial response following treatment with TK inhibitors. Exon 20 insertion mutations in EGFR may be associated with clinical trials (https://clinicaltrials.gov/).

Last updated: 2018-03-06 17:56:01 UTC
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Tier 1
EGFR
Variants
EGFR H773L
EGFR V774M
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

EGFR exon 20 insertion testing identifies a distinct subset of lung adenocarcinomas, accounting for at least 9% of all EGFR-mutated cases and by molecular modeling, are predicted to have potentially different effects on erlotinib binding. Studies show that in contrast to the more classic activating EGFR mutations, these insertions have been associated with de novo resistance to approved EGFR-TKIs (erlotinib and gefitinib). In a recent study, patients with advanced lung adenocarcinoma harboring exon 20 insertions demonstrated no response or partial response following treatment with TK inhibitors. This rare complex mutation (p.H773_V774delinsLM) results in the H773L/V774 mutation compound at the same allele, potentially weakening the inactive state and leading to constitutional activation of EGFR. A recent clinical report suggests this mutation is insensitive to the reversible TKI gefitinib, but can be suppressed by the irreversible TKI osimertinib, leading to sustained disease control (Yang et al., Lung Cancer, 121:1-4, 2018). Exon 20 insertion mutations in EGFR may be associated with clinical trials (https://clinicaltrials.gov/).

Last updated: 2019-01-22 18:50:26 UTC
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Tier 2
EGFR
Variants
EGFR exon(s) 20 insertion
Primary Sites
Brain
Spinal Cord
Brain, Supratentorial
Brain, Infratentorial
Tumor Types
Glioblastoma
Interpretation

In GBM, EGFR mutations typically cluster in the extracellular domain and include in-frame deletions (such as the common “variant III” del 6-273) and missense mutations (A289V, A289D, T263P, G598V). EGFR exon 20 insertions have not been previously reported in GBM. The clinical significance of this mutation with regards to response to anti-EGFR therapy in GBM is unknown. In general, EGFR exon 20 mutations have been reported in approximately 9% of all EGFR-mutated cases of lung cancer and studies show that in contrast to the more classic activating EGFR mutations, these insertions have been associated with de novo resistance or only partial response to approved EGFR-TKIs (erlotinib and gefitinib) in lung cancer.

Last updated: 2015-12-09 23:42:32 UTC
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Tier 1
EGFR
Variants
EGFR D761N
EGFR D761Y
EGFR codon(s) 761 any
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

The EGFR D761 mutation is associated with acquired resistance to EGFR-TKIs (Balak et al., 2006). The functional significance of this alteration is being investigated.

Last updated: 2015-12-09 20:16:10 UTC
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Tier 3
EGFR
Variants
EGFR G863D
Primary Sites
Lung
Stomach
Tumor Types
Adenocarcinoma
Interpretation

A low frequency mutation detected in lung and gastric cancer. Functional significance of this alteration has not yet been described. However, a single NSCLC patient with this mutation in a clinical trial shows partial response to gefitinb therapy

Last updated: 2015-12-09 20:16:16 UTC
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Tier 2
EGFR
Variants
EGFR P753S
Primary Sites
Skin
Tumor Types
Squamous Cell Carcinoma
Interpretation

It is unclear what effect the EGFR P753S varaints has on the EGFR protein. However the location of the variant in the splice site acceptor of Exon 19 may activate the kinase domain. The identification of the EGFR P735S mutation in the context of a dramatic response to cetuximab in a patient with cutaneous squamous cell carcinoma, indicates a new potential pairing of EGFR mutation and targeted therapy for patients with cSCC.

Last updated: 2015-12-09 20:16:21 UTC
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Tier 1
EGFR
Variants
EGFR L861Q
EGFR codon(s) 861 any
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions , EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The L861Q mutation is one of the less common mutations which is an activating mutation that is believed to confer sensitivity to the targeted EGFR tyrosine kinase inhibitors although this mutation may confer reduced response to these inhibitors compared to the more common mutations.

Last updated: 2018-04-06 15:03:01 UTC
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Tier 1
EGFR
Variants
EGFR E709K
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Compound (dual) mutations in EGFR have been previously reported in lung adenocarcinoma and typically include a strong activating mutation combined with a weaker activating mutation. These cases appear to respond well to the EGFR targetted therapies if they include mutations that are known to provide sensitivity to EGFR inhibitor therapies. L858R is a well known activating mutation in exon 21 that is associated with sensitivity to EGFR inhibitors. In vitro functional characterization of mutations at E709 have also been reported to be activivating mutations that are also associated with sensitivity to EGFR inhibitors in vitro. Mutations in E709 often occur together with other muations in EGFR including the L858R mutation.

Last updated: 2015-12-09 20:16:31 UTC
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Tier 2
EGFR
Variants
EGFR E709K
Primary Sites
Spinal Cord
Brain
Brain, Supratentorial
Brain, Infratentorial
Tumor Types
Glioblastoma
Interpretation

In GBM, EGFR mutations typically cluster in the extracellular domain and include in-frame deletions (such as the common “variant III” del 6-273) and missense mutations (A289V, A289D, T263P, G598V). However, the p.E709K mutation in the tyrosine kinase domain of EGFR has not been previously reported in GBM. In vitro functional characterization of mutations at E709 have been reported to be activivating mutations that are associated with sensitivity to EGFR inhibitors in vitro in some cell systems. The clinical significance of this mutation with regards to response to anti-EGFR therapy in GBM is unknown.

Last updated: 2015-12-09 20:16:31 UTC
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Tier 3
FBXW7
Variants
FBXW7 R479Q
FBXW7 D761N
Primary Sites
Breast
Lung
Colon
Stomach
Rectum
Endometrium
Tumor Types
Adenocarcinoma
Interpretation

FBXW7 is a tumor suppressor gene that is mutated in several tumors including colorectal, liver, bladders and ovarian cancers. It is also mutated in endometrial and head and neck squamous cancers. Preclinical data suggest that FBXW7 mutations may sensitize cells to mTOR inhibitors.

Last updated: 2016-06-05 02:49:13 UTC
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Tier 3
FBXW7
Variants
FBXW7 R479Q
FBXW7 D761N
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

FBXW7 is a tumor suppressor gene and is responsible for ubiquitination and turnover of several oncoprotiens. Loss-of-function mutations of FBXW7 lead to constitutive NOTCH1 pathway activation via inhibition of ubiquitin-mediated degradation of activated NOTCH1 and MYC. FBXW7 mutations have been reported in ~3-8% of melanomas. Preclinical data suggest that FBXW7 mutations sensitize cells to mTOR inhibitors. However, advanced tumors with somatic FBXW7 mutations and other concurrent molecular alterations might have limited therapeutic response to mTOR inihibitors. Correlation with other clinical and laboratory findings is recommended.

Last updated: 2017-04-10 18:33:50 UTC
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Tier 2
FGFR3
Variants
FGFR3 Y373C
Primary Sites
Bladder
Tumor Types
Carcinoma
Urothelial Carcinoma
Interpretation

FGFR3 has been found to be mutated in up to 64% of cases of bladder cancer; FGFR3 mutations tend to be exclusive of RAS mutations ,TP53 overexpression, TP53 mutation, but not PIK3CA mutations. However, subsets of cases with co-mutations have been described. FGFR3 mutations (including Y373C) are believed to lead to constitutive activation of the receptor and activation of the RAS-MAPK pathway. FGFR3 mutations are often seen in non-muscle invasive bladder cancers and tend to correlate with low stage and grade; however FGFR3 mutations have also been described in muscle-invasive bladder cancer. Targeted therapies with FGFR3 inhibitors have been explored in patients with bladder cancer.

Last updated: 2015-12-09 20:59:33 UTC
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Tier 2
GNAS
Variants
GNAS codon(s) 201, 844 any
Primary Sites
Lung
Kidney
Tumor Types
Adenocarcinoma
Interpretation

This GNAS mutation causes constitutive activation of the G-protein complex and activates adenylate cyclase to produce cyclic-AMP (cAMP) that can activate oncogenic pathways. The R201 mutation in GNAS was thought to both drive tumor progression and confer exceptional chemo-sensitivity in a patient with an unclassified kidney cancer.

Last updated: 2019-04-30 14:30:45 UTC
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Tier 2
HRAS
Variants
HRAS codon(s) 12, 13, 61 any
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

When mutated, HRAS can act as an oncogene, causing normal cells to become cancerous. Somatic HRAS mutations have been associated with some cases of bladder, thyroid and kidney cancers and in nevi. Based on clinical evidence in melanoma with the related family member NRAS, downstream pathway MEK inhibitors may be a feasible treatment strategy. The effectiveness of MEK inhibitors for HRAS-mutant thyroid and bladder cancer patients has not yet been investigated.

Last updated: 2015-12-09 20:17:06 UTC
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Tier 1
HRAS
Variants
HRAS codon(s) 12, 13, 61 any
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Follicular Carcinoma
Medullary Carcinoma
Interpretation

RAS is a family of small GTPases and acts as an oncogene. Point mutations in codons 12 and 13 of RAS gene increases its affinity for GTP and those in codon 61 inactivate its autocatalytic GTPase function, resulting in permanent RAS activation and stimulation of its downstream targets along the MAPK and PI3K/AKT signaling pathways. In thyroid, RAS (HRAS, NRAS and KRAS) mutations are identified in 10--20% of papillary carcinomas, 40--50% of follicular carcinomas, 10% of medullary carcinomas, and 20--40% of poorly differentiated and anaplastic carcinomas. The frequency of HRAS mutations in thyroid carcinomas is approximately 4%. HRAS mutations at codon 61 have been reported in a variety of thyroid lesions and are especially prevalent in the follicular variant of papillary thyroid carcinoma. However, the predictive or prognostic significance of HRAS mutation in thyroid carcinoma is not clear and correlation with other clinical and laboratory findings is necessary.

Last updated: 2018-03-12 15:33:36 UTC
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Tier 2
HRAS
Variants
HRAS codon(s) 12, 13, 61 any
Primary Sites
Bladder
Tumor Types
Urothelial Carcinoma
Interpretation

When mutated, HRAS can act as an oncogene. Somatic HRAS mutations have been associated with some cases of upper and lower urinary tract urothelial carcinoma, thyroid, and kidney cancers and in nevi. The frequency of HRAS mutations in upper and lower urinary tract urothelial carcinoma are about 10%. Interestingly, it has been shown that the HRAS mutation in lower urinary tract urothelial carcinoma may occur in tumors without FGFR3 mutations.

Last updated: 2016-04-17 17:47:49 UTC
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Tier 1
IDH1
Variants
IDH1 R132H
IDH1 R132L
IDH1 R132C
IDH1 codon(s) 132 any
Primary Sites
Spinal Cord
Brain
Brain, Supratentorial
Brain, Infratentorial
Tumor Types
Glioblastoma
Astrocytoma, Anaplastic
Oligodendroglioma
Astrocytoma, Diffusely Infiltrating
Infiltrating Glioma, NOS
Neuroepithelial neoplasm, high grade
Neuroepithelial Neoplasm, NOS
Glioma
High Grade Glioma
Oligodendroglioma, Anaplastic
Interpretation

IDH1 or IDH2 mutations are found in >70% of lower grade diffusely infiltrative gliomas and in >90% of secondary glioblastoma. IDH mutational status has been reported to be a favorable prognostic indicator relative to wild-type gliomas of similar histology, regardless of grade. Therapeutic strategies exploiting mutated IDH protein, including through direct inhibition and vaccine-based approaches, are currently the subject of preclinical research and clinical trials.

Last updated: 2021-12-03 18:06:37 UTC
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Tier 2
IDH1
Variants
IDH1 R132H
IDH1 R132L
IDH1 R132C
IDH1 codon(s) 132 any
Primary Sites
Breast
Tumor Types
Adenocarcinoma
Interpretation

IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies. A case of an IDH1 p.R132L mutation in a patient with hormone receptor-positive (HR+) breast adenocarcinoma has been reported (5). IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma, suggesting future avenues for disease monitoring through noninvasive measurement of 2-HG, as well as for the development and study of targeted therapies against the aberrant IDH1 enzyme.

Last updated: 2015-12-09 20:17:33 UTC
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Tier 2
IDH1
Variants
IDH1 R132L
IDH1 codon(s) 132 any
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies including AML, central nervous system and billary tract. Strikingly, IDH1 mutations were rarely detected in the other solid tumor types. Reports have shown that melanoma cases can harbor IDH1 mutations. An IDH1 R132C mutation was found in a melanoma metastasis to the lung. IDH1 mutations were found to coexist with BRAF or KIT mutations, and all were detected in metastatic lesions. Coexistence of IDH1 R132C mutation with KRAS has also been reported in a single case of lung adenocarcinoma (Sequist et al., Ann Oncol., 22:2616-2624, 2011). The clinical significance of this mutation with regards to response to anti-IDH1 therapy in lung cancer is unknown.

Last updated: 2020-07-24 14:51:58 UTC
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Tier 2
IDH1
Variants
IDH1 R132C
IDH1 codon(s) 132 any
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

Reports have shown that melanoma cases can harbor IDH1 mutations. An IDH1 R132C mutation was found in a melanoma metastasis to the lung. IDH1 mutations were found to coexist with BRAF or KIT mutation, and all IDH1 mutations were detected in metastatic lesions. BRAF-mutated melanoma cells, additionally expressing the cancer-related IDH1 mutant have been shown to have increased colony-forming and in vivo growth activities.

Last updated: 2015-12-09 20:17:33 UTC
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Tier 1
IDH2
Variants
IDH2 R140Q
IDH2 R172K
IDH2 codon(s) 140, 172 any
Primary Sites
Spinal Cord
Brain
Brain, Supratentorial
Brain, Infratentorial
Tumor Types
Glioblastoma
Astrocytoma, Anaplastic
Ependymoma
Oligodendroglioma
Interpretation

IDH1 or IDH2 mutations are found in >70% of lower grade diffusely infiltrative gliomas and in >90% of secondary glioblastoma. IDH mutational status has been reported to be a favorable prognostic indicator relative to wild-type gliomas of similar histology, regardless of grade. Therapeutic strategies exploiting mutated IDH protein, including through direct inhibition and vaccine-based approaches, are currently the subject of preclinical research and clinical trials.

Last updated: 2017-01-20 03:26:51 UTC
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Tier 3
KIT
Variants
KIT M541L
Primary Sites
Stomach
Small Intestine
Tumor Types
Gastrointestinal Stromal Tumor
Interpretation

The M541L mutation has been implicated in hematological malignancies. It may help to identify a subgroup of cases who may benefit from low dose imatinib therapy. KIT mutations are also associated with Gastro Intestinal Stromal Tumors. The KIT variant M541L was originally thought to be associated with increased risk of certain tumors such as aggressive fibromatosis (AF; Dufresne et al., 2010). However, larger scale studies have shown that the prevalence of this mutation within AF does not differ from that of the general population and this variant was not found to be tumor-specific, classifying it as a single nucleotide polymorphism and non-pathogenic (Grabellus et al., 2011).

Last updated: 2016-10-11 21:40:16 UTC
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Tier 1
KIT
Variants
KIT E554K
Primary Sites
Stomach
Small Intestine
Tumor Types
Gastrointestinal Stromal Tumor
Interpretation

Approximately 50-60% of the oncogenic mutations in Gastrointestinal stromal tumors (GIST) are present in Exon 11 of the KIT gene. The E554K variant is present in Exon 11 of the KIT gene. Identification of GIST genotype is important given the availability of targeted therapy with KIT/PDGFRA tyrosine kinase inhibitors (eg, imatinib, sunitinib, etc).

Last updated: 2016-10-11 21:39:10 UTC
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Tier 1
KIT
Variants
KIT V560D
KIT exon(s) 11 any
Primary Sites
Stomach
Small Intestine
Tumor Types
Gastrointestinal Stromal Tumor
Interpretation

KIT mutations occur in approximately 80% of patients with gastrointestinal stromal tumors. The major region of KIT mutation in GIST is within exon 11, occurring in about 65% of patients. KIT exon 11 mutations are activating mutations and are typically sensitive to treatment with Imatinib.

Last updated: 2016-10-11 21:39:37 UTC
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Tier 1
KIT
Variants
KIT N822K
KIT exon(s) 17 any
Primary Sites
Anus
Tumor Types
Melanoma
Interpretation

KIT mutations occur in approximately 15-20% of patients with mucosal melanomas. The majority ofKIT mutations occur within exon 11 and they are less frequent in other exons. The N822K mutation in exon 17 occurs within the kinase domain of KIT. Mutant KIT proteins have increased kinase activity and transforming activity in vitro. Although KIT activating mutations in exons 11 and 13 are typically sensitive to treatment with Imatinib, there was no response to treatment noted in patients harboring mutations in exon 17 (Ref. 4).

Last updated: 2018-04-06 15:06:14 UTC
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Tier 1
KRAS
Variants
KRAS G12A
KRAS G12V
KRAS G12D
KRAS G12C
KRAS G12S
KRAS G12R
KRAS G13C
KRAS G13S
KRAS G13R
KRAS Q61H
KRAS Q61L
KRAS Q61K
KRAS Q61R
KRAS A146T
KRAS A146V
KRAS A146P
KRAS A11V
KRAS codon(s) 12, 13, 61, 117, 146 any
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Carcinoma
Interpretation

KRAS is a gene that encodes one of the several proteins in the epidermal growth factor receptor (EGFR) signaling pathway that is important in the development and progression of cancer. KRAS can harbor oncogenic mutations that yield a constitutively active protein. Such mutations are found in approximately 30% to 50% of metastatic colorectal tumors and are common in other tumor types. Mutations in the KRAS gene may indicate poor prognosis and poor drug response with therapies targeted to EGFR. The absence of a KRAS mutation predicts a greater likelihood of response to EGFR-targeted therapies and improved survival with such treatment. The relevant KRAS mutation is in one of five codons (12 13, 61, 117 or 146). The presence of KRAS mutations in codon 12, 13 or 61 is associated with a high likelihood of resistance to therapies targeting EGFR. In addition, mutations at codons 117 and 146 may also be associated with reduced response to EGFR-targeted therapies. Results should be interpreted in conjunction with other laboratory and clinical findings. Drug resistance: Panitumumab Cetuximab

Last updated: 2020-01-25 17:53:49 UTC
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Tier 2
KRAS
Variants
KRAS G12A
KRAS G12V
KRAS G12D
KRAS G12C
KRAS G12S
KRAS G12R
KRAS G13D
KRAS G13C
KRAS G13S
KRAS G13R
KRAS Q61H
KRAS Q61L
KRAS Q61K
KRAS Q61R
KRAS codon(s) 12, 13, 61, 117, 146 any
Primary Sites
Lung
Tumor Types
Squamous Cell Carcinoma
Interpretation

KRAS belongs to the RAS family of oncogenes. In lung, KRAS mutations are detected in approximately 20% to 25% of adenocarcinoma and less than 10% of squamous cell carcinoma which demonstrate a minor glandular component. KRAS mutations in NSCLC most often occur in codons 12 or 13 and with a lower frequency in codon 61. Mutations in KRAS are usually mutually exclusive with other oncogenic driver aberrations including EGFR, BRAF, HER2 mutations and ALK and ROS1 rearrangements. Contrary to most other oncogenic driver mutations, KRAS is more often found in smokers and is detected at lower frequency in East Asian patient cohorts. The prognostic as well as predictive role of KRAS mutations continues to be studied. Although various attempts inhibiting KRAS have been made, there is no established therapy specific for this large patient subpopulation. Recommend correlation with other clinical and lab findings.

Last updated: 2016-10-05 22:34:23 UTC
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Tier 2
KRAS
Variants
KRAS G12A
KRAS G12V
KRAS G12D
KRAS G12C
KRAS G12S
KRAS G12R
KRAS G13D
KRAS G13C
KRAS G13S
KRAS G13R
KRAS Q61H
KRAS Q61L
KRAS Q61K
KRAS Q61R
KRAS codon(s) 12, 13, 61, 117, 146 any
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Pleomorphic Carcinoma
Carcinoma
Non-Small Cell Lung Carcinoma
Interpretation

KRAS belongs to the RAS family of oncogenes. KRAS mutations are detected in approximately 20% to 25% of lung adenocarcinoma. Contrary to most other oncogenic driver mutations, KRAS is more often found in smokers and is detected at lower frequency in East Asian patient cohorts. Mutations in KRAS are usually mutually exclusive with other oncogenic driver aberrations including EGFR, BRAF, HER2 mutations and ALK and ROS1 rearrangements. KRAS mutations in NSCLC most often occur in codons 12 or 13 and with a lower frequency in codon 61. The prognostic as well as predictive role of KRAS mutations continues to be studied. Although various attempts inhibiting KRAS have been made, there is no established therapy specific for this large patient subpopulation.

Last updated: 2021-12-30 20:04:08 UTC
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Tier 2
KRAS
Variants
KRAS G12A
KRAS G12V
KRAS G12D
KRAS G12C
KRAS G12S
KRAS G12R
KRAS G13D
KRAS G13C
KRAS G13S
KRAS G13R
KRAS Q61H
KRAS Q61L
KRAS Q61K
KRAS Q61R
KRAS A146T
KRAS A146V
KRAS A146P
KRAS A11V
KRAS codon(s) 12, 13, 61, 117, 146 any
Primary Sites
Pancreas
Tumor Types
Adenocarcinoma
Carcinoma
Interpretation

Pancreatic ductal adenocarcinoma (PDAC) is initiated by oncogenic mutant KRAS, which has been shown to drive pancreatic neoplasia. More than 90% of pancreatic ductal adenocarcinoma samples have a KRAS mutation which may have prognostic, and (with ongoing trials assessing the efficacy of novel KRAS inhibitors) possibly therapeutic implications. However, targeting KRAS directly has been difficult in these tumors.

Last updated: 2019-05-28 17:40:59 UTC
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Tier 2
KRAS
Variants
KRAS G12D
KRAS codon(s) 12 any
Primary Sites
Gall Bladder
Tumor Types
Adenocarcinoma
Interpretation

KRAS belongs to the RAS family of oncogenes. KRAS mutations have been described in approximately 3-40% gall bladder adenocarcinomas (more often in East Asia). The prognostic and therapeutic implications of KRAS mutations in gall bladder adenocarcinomas continue to be explored.

Last updated: 2020-07-24 14:52:02 UTC
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Tier 2
MET
Variants
MET V1110I
MET M1131T
MET M1149T
MET V1188L
MET L1195V
MET V1220I
MET L1213F
Primary Sites
Kidney
Tumor Types
Papillary Renal Cell Carcinoma
Interpretation

Activating somatic mutations in the tyrosine kinase domain of MET are found in about 10-15% of sporadic papillary renal cell carcinoma (pRCC). MET mutations are predominantly associated with Type 1 pRCC tumors. The responses to foretanib an oral inhibitor of MET and other tyrosine kinases including VEGFR2, have been described in patients with papillary renal cell cancer.

Last updated: 2020-07-24 14:52:06 UTC
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Tier 2
MET
Variants
MET H1112Y
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Nonsynonymous mutations in the MET gene have been described in non-small cell lung cancer (NSCLC) and (small cell lung cancer) SCLC. Increased expression of MET protein was associated with improved progression free survival and overall survival in patients who received MetMAb (an anti-MET antibody) and erlotinib. The activity of MET inhibitors in NSCLC or SCLC tumors with non-kinase domain MET mutations is not yet known.

Last updated: 2019-02-14 20:04:39 UTC
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Tier 3
MET
Variants
MET E168D
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

The MET p. E168D mutation has been reported in various tumors including lung cancer according to the COSMIC database. Some studies indicate that this mutation may be associated with higher affinity for ligand, HGF. In vitro studies in cell lines with cells expressing MET p.E168D may show increased sensitivity to MET inhibitor. According to ClinVar, this particular variant is a likely benign germline variant (https://preview.ncbi.nlm.nih.gov/clinvar/variation/41627/). The clinical significance of this variant remains to be fully elucidated.

Last updated: 2019-02-22 18:05:13 UTC
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Tier 3
MET
Variants
MET T1010I
Primary Sites
Lung
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

The MET p.T1010I variant has been reported in some tumor types and also has been reported as a germline variant present in less than 1% of the general population. Its role in tumor development and progression continues to be studied. The utility of MET pathway inhibitors also continues to be explored.

Last updated: 2015-12-09 20:20:41 UTC
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Tier 3
MET
Variants
MET M1268T
Primary Sites
Kidney
Tumor Types
Adenocarcinoma
Interpretation

A subset of sporadic papillary renal carcinomas were caused by activating mutations in the tyrosine kinase domain of the MET proto-oncogene. Several of the MET mutations (M1268T, D1246 and V11101) were located in codons homologous to codons mutated in other protein receptor tyrosine kinases (Ret M918T, Kit D816V, and c-erbB V1571)

Last updated: 2015-12-09 20:20:48 UTC
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Tier 3
MLH1
Variants
MLH1 V384D
Primary Sites
Lung
Colon
Rectum
Tumor Types
Adenocarcinoma
Carcinoma
Interpretation

The MLH1 V384D polymorphism has been associated with cancer risk in some tumor types. In addition, according to one report, MLH1 V384D polymorphism has been reported to be associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions for those patients. The effect of this MLH1 polymorphism when present with other EGFR-TKI sensitizing mutations such as Exon 19 deletions in EGFR remains to be clarified. Some studies have shown that patients carrying the MLH1 V384D variant have an increased risk of the development of microsatellite-instable as well as -stable colorectal cancer. This variant has an allele frequency of 4% in the East Asian population. Of note, this variant is reported as a benign germline variant in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/41632/). Clinical correlation is recommended.

Last updated: 2018-05-09 21:13:25 UTC
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Tier 1
NRAS
Variants
NRAS G12A
NRAS G12V
NRAS G12D
NRAS G12C
NRAS G12S
NRAS G12R
NRAS G13D
NRAS G13C
NRAS G13S
NRAS G13R
NRAS G13A
NRAS G13V
NRAS Q61H
NRAS Q61L
NRAS Q61K
NRAS Q61R
NRAS codon(s) 12, 13, 61, 146 any
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

NRAS mutations occur in approximately 1--6% of colorectal cancers. Several studies have shown that patients with NRAS-mutated tumors are less likely to respond to cetuximab or panitumumab, but this may not have an effect on PFS or overall survival.

Last updated: 2019-04-05 15:39:05 UTC
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Tier 1
NRAS
Variants
NRAS G12A
NRAS G12V
NRAS G12D
NRAS G12C
NRAS G12S
NRAS G12R
NRAS G13D
NRAS G13C
NRAS G13S
NRAS G13R
NRAS G13A
NRAS G13V
NRAS Q61H
NRAS Q61L
NRAS Q61K
NRAS Q61R
NRAS codon(s) 12, 13, 61, 146 any
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

Somatic mutations in NRAS have been found in approximately 13-25% of all malignant melanomas. The result of these mutations is constitutive activation of NRAS signaling pathways. NRAS mutations are found in all melanoma subtypes, but may be slightly more common in melanomas derived from chronic sun-damaged (CSD) skin . Currently, there are no direct anti-NRAS therapies available.

Last updated: 2020-07-24 14:53:31 UTC
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Tier 1
NRAS
Variants
NRAS G12A
NRAS G12V
NRAS G12D
NRAS G12C
NRAS G12S
NRAS G12R
NRAS G13D
NRAS G13C
NRAS G13S
NRAS G13R
NRAS G13A
NRAS G13V
NRAS codon(s) 12, 13, 61, 146 any
Primary Sites
Thyroid
Tumor Types
Follicular Carcinoma
Papillary Carcinoma
Interpretation

RAS mutations (HRAS, NRAS and KRAS) are found in all epithelial thyroid malignancies. The frequency of HRAS mutations in thyroid carcinomas is 4%. RAS mutations are identified in 10-20% of papillary carcinomas, 40-50% of follicular carcinomas and 20-40% of poorly differentiated and anaplastic carcinomas .

Last updated: 2020-07-24 14:53:44 UTC
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Tier 1
NRAS
Variants
NRAS Q61H
NRAS Q61L
NRAS Q61K
NRAS Q61R
Primary Sites
Thyroid
Tumor Types
Follicular Carcinoma
Papillary Carcinoma
Interpretation

NRAS gene belongs to the family of RAS genes. It encodes a G protein that is important in the transmission of growth-promoting signals from the cell surface receptors to the nucleus through RAS-RAF- mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)-AKT cell signaling pathways. NRAS mutations are the most common type of RAS mutations in thyroid nodules. Activating point mutations in NRAS gene have been associated with follicular-patterned neoplasms including follicular adenoma, follicular carcinoma and follicular variant papillary thyroid carcinoma cases. NRAS mutations have been also detected in a subset of poorly differentiated carcinoma and anaplastic carcinoma. NRAS mutations concentrate in codon 61, while those in codons 12 or 13 are rare. According to some studies, there is a significant correlation between RAS mutations and distant bone metastases among follicular and papillary carcinomas. However, RAS mutations are also frequently found in encapsulated follicular variant of papillary carcinoma, a tumor with an indolent behavior. Clinical correlation is recommended.

Last updated: 2016-06-25 19:38:54 UTC
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Tier 1
NRAS
Variants
NRAS G12A
NRAS G12V
NRAS G12D
NRAS G12C
NRAS G12S
NRAS G12R
NRAS G13D
NRAS G13C
NRAS G13S
NRAS G13R
NRAS G13A
NRAS G13V
NRAS Q61H
NRAS Q61L
NRAS Q61K
NRAS Q61R
NRAS codon(s) 12, 13, 61, 146 any
Primary Sites
Thyroid
Tumor Types
Interpretation

RAS mutations have also been identified in benign Follicular Adenomas(FA); however, it is unclear whether RAS positive FA have a higher chance of progression to cancer. The prevalence of this mutation in benign thyroid nodules is between 20 and 40%. The low overall prevalence of RAS mutations in thyroid cancers and the relatively high mutation rate in benign nodules makes ras mutation analysis unsuitable as a standalone test to predict malignancy in indeterminate thyroid nodules.

Last updated: 2015-12-09 20:21:38 UTC
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Tier 2
NRAS
Variants
NRAS G12A
NRAS G12V
NRAS G12D
NRAS G12C
NRAS G12S
NRAS G12R
NRAS G13D
NRAS G13C
NRAS G13S
NRAS G13R
NRAS G13A
NRAS G13V
NRAS Q61H
NRAS Q61L
NRAS Q61K
NRAS Q61R
NRAS codon(s) 12, 13, 61, 146 any
NRAS T58I
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Non-Small Cell Lung Carcinoma
Interpretation

NRAS is a member of the RAS family of oncogenes and activating mutations of NRAS have been reported in about 1% of NSCLCs and are mostly exclusive of other known driver mutations. The Q61 codon is most frequently affected. In preclinical studies, cell lines harboring NRAS mutation(s) showed variable sensitivities to pathway inhibitors.

Last updated: 2019-01-22 18:51:07 UTC
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Tier 2
NRAS
Variants
NRAS Q61R
NRAS G12D
Primary Sites
Liver
Tumor Types
Cholangiocarcinoma
Interpretation

NRAS is a member of the RAS family of oncogenes and activating mutations of NRAS have been reported in a wide variety of tumors including occasional cases of cholangiocarcinomas.

Last updated: 2015-12-09 20:21:38 UTC
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Tier 2
NRAS
Variants
NRAS G12A
NRAS G12V
NRAS G12D
NRAS G12C
NRAS G12S
NRAS G12R
NRAS G13D
NRAS G13C
NRAS G13S
NRAS G13R
NRAS G13A
NRAS G13V
NRAS Q61H
NRAS Q61L
NRAS Q61K
NRAS Q61R
NRAS codon(s) 12, 13, 61, 146 any
Primary Sites
Bladder
Tumor Types
Urothelial Carcinoma
Interpretation

NRAS is a member of the RAS family of oncogenes and activating mutations of NRAS have been reported in a wide variety of tumors including occasional cases of bladder cancer. This finding may influence targeted therapy options.

Last updated: 2017-01-20 03:27:37 UTC
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Tier 1
PDGFRA
Variants
PDGFRA D842V
PDGFRA codon(s) 842 any
Primary Sites
Stomach
Small Intestine
Tumor Types
Gastrointestinal Stromal Tumor
Interpretation

The D842V mutation results in an amino acid substitution at position 842 in PDGFRA, from an aspartic acid (D) to a valine (V). This mutation occurs within the TK2 domain. PDGFRA D842V mutation has been found in a distinct subset of GIST, typically from the stomach. The D842V mutation is known to be associated with tyrosine kinase inhibitor resistance. Recent evidence has shown that Dasatinib has been also recently associated with promising clinical activity in patients with advanced GIST carrying exon 18 mutation of the PDGFRA gene (including the D842V mutation). Interestingly, recent in vitro data have suggested that crenolanib, a highly selective and potent inhibitor of both PDGFRA and PDGFRB, blocks phosphorylation of D842V mutant PDGFRA at clinically achievable concentrations

Last updated: 2016-10-11 21:39:58 UTC
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Tier 1
PIK3CA
Variants
PIK3CA E542K
PIK3CA E545K
PIK3CA H1047R
PIK3CA codon(s) 542, 545, 1047 any
Primary Sites
Breast
Tumor Types
Adenocarcinoma
Lobular Carcinoma
Interpretation

PIK3CA mutations activate the PI3K-PTEN-AKT pathway which is downstream from both the EGFR and the RAS-RAF-MAPK pathways.The somatic mutations found thus far in PIK3CA are oncogenic, and the majority of them are clustered within exon 9 and 20 (helical and kinase domains), with 80% of the identified mutations found within three hotspot: E542K, E545K, and H1047R. PIK3CA mutations are often found in hormone receptor positive breast cancer and have been associated with resistance to anti-EGFR therapy in some studies but not in others.

Last updated: 2017-01-20 03:27:58 UTC
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Tier 2
PIK3CA
Variants
PIK3CA exon(s) 10, 20, 21 any
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations in PIK3CA have been found in 10-30% of colorectal cancers. According to some reports, co-occurrence of both exon 9 and exon 20 PIK3CA mutations, when present, may be associated with a poor prognosis. Recent 'molecular pathological epidemiology' (MPE) research has shown that aspirin use is associated with better prognosis and clinical outcome in PIK3CA-mutated colorectal carcinoma, suggesting somatic PIK3CA mutation may be a molecular biomarker that predicts response to aspirin therapy. PIK3CA may also be a target of directed therapy in some clinical settings.

Last updated: 2020-07-24 14:52:12 UTC
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Tier 2
PIK3CA
Variants
PIK3CA exon(s) 10, 20, 21 any
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Carcinoma
Interpretation

Somatic mutations in PIK3CA are seen in approximately 2% of papillary thyroid carcinoma, poorly differentiated carcinoma, anaplastic carcinoma. Somatic mutations of PIK3CA have been described particularly in advanced and dedifferentiating thyroid tumors. Their prevalence varies from 16 to 23% in anaplastic thyroid carcinomas. They are less frequent in papillary and follicular thyroid carcinomas and the prevalence in medullary thyroid carcinomas remains unknown. Although inhibitors of the PI3K/AKT/mTOR pathway have shown efficacy against thyroid cancer in pre-clinical models, their success in clinical trials remains to be determined.

Last updated: 2015-12-09 20:21:59 UTC
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Tier 2
PIK3CA
Variants
PIK3CA exon(s) 10, 20, 21 any
Primary Sites
Brain
Tumor Types
Interpretation

PIK3CA mutations have been identified in pediatric and adult gliomas including: anaplastic oligodendrogliomas, anaplastic astrocytomas, glioblastoma multiforme, rosette forming glioneuronal tumors and medulloblastomas. PIK3CA mutations provide a mechanism for disrupting the PI3K/Akt pathway.

Last updated: 2015-12-09 20:21:59 UTC
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Tier 2
PIK3CA
Variants
PIK3CA exon(s) 10, 20, 21 any
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Squamous Cell Carcinoma
Interpretation

Somatic mutations in PIK3CA have been found in 1–3% of NSCLC. These mutations typically occur within specific hotspot regions. PIK3CA mutations appear to be more common in squamous cell histology compared to adenocarcinoma and can occur with or without a history of smoking. PIK3CA mutations can co-occur with EGFR mutations and PIK3CA mutations have been detected in a small percentage (approximately 5%) of EGFR-mutated lung cancers with acquired resistance to EGFR TKI therapy.

Last updated: 2016-02-11 21:44:04 UTC
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Tier 2
IDH1
Variants
IDH1 R132H
IDH1 R132L
IDH1 R132C
IDH1 codon(s) 132 any
Primary Sites
Liver
Tumor Types
Cholangiocarcinoma
Interpretation

IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies. Mutations in IDH1 and IDH2 have been reported in intrahepatic cholangiocarcinomas. IDH1 mutation has been associated with highly elevated tissue levels of the enzymatic product 2-hydroxyglutarate. IDH1 mutation has been described to be a feature of intrahepatic cholangiocarcinomas.

Last updated: 2016-06-07 02:05:32 UTC
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Tier 2
HRAS
Variants
HRAS codon(s) 12, 13, 61 any
HRAS Q61R
Primary Sites
Breast
Tumor Types
Cholangiocarcinoma
Interpretation

When mutated, HRAS can act as an oncogene, causing normal cells to become cancerous. Somatic HRAS mutations have been associated with some cases of bladder, thyroid and kidney cancers and in nevi. HRAS mutations are rarely found in the breast and the HRAS Q61R mutation has not been previously reported in this cancer. Inferring the clinical evidence seen in melanoma, downstream pathway MEK inhibitors may be a feasible treatment strategy. The effectiveness of MEK inhibitors for HRAS-mutant thyroid and bladder cancer patients has not yet been investigated.

Last updated: 2015-12-09 21:04:41 UTC
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Tier 3
MET
Variants
MET E168D
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Interpretation

MET is a member of the receptor tyrosine kinase and proto-oncogene playing a major role in tumor development and metastasis. MET E168D has been previously reported in papillary thyroid carcinoma. This mutation is located in the SEMA domain containing the ligand binding site. In vitro study has shown that E168D alters MET functionality in lung cancer. The prognostic and predictive significance of MET mutations in thyroid cancer is not clear and correlation with other clinical and laboratory findings is necessary. Of note, this variant is reported as a likely benign germline variant in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/41627/).

Last updated: 2018-10-05 18:06:21 UTC
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Tier 2
PIK3CA
Variants
PIK3CA codon(s) 542, 545, 1047 any
Primary Sites
Bladder
Kidney
Ureter
Tumor Types
Urothelial Carcinoma
Interpretation

PIK3CA mutations activate the PI3K-PTEN-AKT pathway which is downstream from both the EGFR and the RAS-RAF-MAPK pathways.The somatic mutations found thus far in PIK3CA are oncogenic, and the majority of them are clustered within exon 9 and 20 (helical and kinase domains). Activating mutations in PIK3CA are found are found in a wide variety of human cancers including 27% urothelial bladder cancers, with a higher prevalence in low grade tumors. Up to 13.6% of renal pelvic urothelial carcinomas also harbor activating somatic mutations in PIK3CA gene. The role of PIK3CA mutations as prognosticators of outcome or predictors of therapeutic response awaits further evaluation.

Last updated: 2018-05-16 16:40:23 UTC
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Tier 2
PTEN
Variants
PTEN any deletion
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

PTEN mutations occur in 5-14% of colorectal cancers. PTEN is a tumor suppressor gene, and loss of PTEN results in upregulation of the PI3K/ AKT pathway. PTEN loss of expression is observed with KRAS, BRAF, and PIK3CA mutations. In retrospective studies, PTEN loss is associated with decreased sensitivity of colorectal cancer tumors to anti-EGFR antibodies. PTEN loss is associated with lack of benefit of the anti-EGFR antibody, cetuximab.

Last updated: 2020-07-24 14:52:16 UTC
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Tier 2
PTEN
Variants
PTEN any frameshift
PTEN any deletion
Primary Sites
Thyroid
Tumor Types
Follicular Carcinoma
Papillary Carcinoma
Interpretation

PTEN is an obligate haplo-insufficient tumor suppressor gene and is mutated in a large number of cancers. It encodes a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/mTOR signaling pathway. Cancer-associated alterations in this gene often result in loss of PTEN protein and upregulation of the PI3K/AKT/mTOR pathway. PTEN mutations have been reported in 15% of anaplastic thyroid cancer. Germline mutations of PTEN lead to inherited hamartoma and Cowden syndrome. Patients with Cowden syndrome have an increased risk of developing epithelial thyroid cancer, follicular carcinoma being the most common, of up to 10% compared to <1% in the general population. Clinical trials using PI3K-beta inhibitor are available for patients with PTEN-deficient tumors.

Last updated: 2016-08-31 22:06:12 UTC
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Tier 2
PTEN
Variants
PTEN any frameshift
PTEN any deletion
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations in PTEN have been found in 4-8% of non-small cell carcinomas (NSCLC) including adenocarcinomas and squamous cell carcinomas. PTEN is a tumor suppressor gene, and loss of PTEN results in upregulation of the PI3K/ AKT pathway. Loss of PTEN is most commonly due to promoter hypermethylation, while homozygous deletion and nonsense mutations with loss of heterozygosity (LOH) may also occur. PTEN mutations may occur in multiple exons. In preclinical studies, PTEN loss is associated with decreased sensitivity of EGFR mutant lung tumors to EGFR TKIs. Clinical trials assessing the efficacy of PI3K inhibitors in PTEN loss are being explored.

Last updated: 2020-07-24 14:52:22 UTC
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Tier 3
RB1
Variants
Primary Sites
Eye
Tumor Types
Retinoblastoma
Interpretation

The RB1 protein is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma - See more at: http://www.cancerindex.org/geneweb/RB1.htm#sthash.uzBqWCrJ.dpuf

Last updated: 2016-10-11 21:33:42 UTC
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Tier 3
SMAD4
Variants
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members  SMAD4. The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively. Somatic SMAD4 mutations have been reported to be more common in advanced stages of CRCs and LOH at the SMAD4 locus has been associated with poor prognosis. SMAD4 mutations were associated with mucinous histology.

Last updated: 2015-12-09 21:27:16 UTC
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Tier 2
SMAD4
Variants
SMAD4 any nonsense
Primary Sites
Pancreas
Tumor Types
Adenocarcinoma
Interpretation

SMAD4 is a tumor suppressor gene that is mutated in one third of colorectal cancer and half of pancreatic tumors. SMAD4 inactivation by allelic deletion or mutation mainly occurs in late stage pancreatic ductal adenocarcinoma and is associated with poorer prognosis. SMAD4 loss increased resistance to the chemotherapeutic agent 5'-fluorouracil.

Last updated: 2018-04-25 15:22:12 UTC
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Tier 3
SMAD4
Variants
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Homozygous mutations causing SMAD4 loss are found in approximately 3% of lung adenocarcinomas and squamous cell carcinomas cases. SMAD4 loss tends to act synergistically with TP53 and KRAS mutations to increase lymphatic metastasis and tumor size. Experimental work in a mouse model has demonstrated increased susceptibility to DNA topoisomerase inhibitors with homozygous SMAD4 loss of function mutation coupled with KRAS G12D activating mutations.

Last updated: 2016-04-21 21:05:22 UTC
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Tier 1
EGFR
Variants
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Based on reports in the literature, EGFR and KRAS mutations can occasionally coexist in the same bronchial-pulmonary carcinoma. The biological implications of this coexistence are still poorly understood mainly because these cases are not frequent. It is therefore necessary to study larger series of cases with the two mutations to better understand the biological, clinical and therapeutic implications. Patients with coexisting EGFR and KRAS variants may have a partial response to EGFR TKI.

Last updated: 2015-12-09 21:32:55 UTC
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Tier 2
ERBB2
Variants
ERBB2 V842I
Primary Sites
Breast
Tumor Types
Adenocarcinoma
Interpretation

ERBB2 V842I is a mutation identified in breast cancer patients, located within the kinase domain, which increases kinase activity, in vitro, and increases the number of colonies formed in soft agar. Cells with this mutation display an invasive morphology, but tumor xenografts formed from these cells do not grow more rapidly than those with wild-type HER2. When assessing sensitization to HER2-targeted therapies in vitro, cells with this mutation are highly sensitive to neratinib but less sensitive to lapatinib, in a manner similar to wild-type HER2.

Last updated: 2016-06-07 02:14:02 UTC
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Tier 2
EGFR
Variants
EGFR copy number gain
Primary Sites
Brain
Brain, Infratentorial
Brain, Supratentorial
Tumor Types
Glioblastoma
Interpretation

Greater than 40% of glioblastomas (GBM) harbor focal amplification of the EGFR locus and there is evidence to suggest that these are driver alterations in these patients, making the EGFR pathway a potential therapeutic target in some clinical settings. Moreover, this alteration is relatively specific for GBM with very few other diffusely infiltrative gliomas having been shown to carry focal amplification of this locus (<3%). In GBM, this alteration frequently occurs in combination with other alterations of EGFR including polysomy 7, intragenic inframe deletions (e.g. EGFRvIII), and/or somatic point mutations. Based on current evidence, the independent predictive value of EGFR amplification in GBM is unclear. The relationship between individual and concurrent EGFR alterations and clinical response to small molecular inhibitors targeting EGFR is currently under investigation in clinical trials.

Last updated: 2016-10-11 21:41:07 UTC
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Tier 1
NOTCH2
Variants
NOTCH2 I2304fs
NOTCH2 exon(s) 34 frameshift
Primary Sites
Spleen
Tumor Types
Marginal Zone B Cell Lymphoma
Interpretation

NOTCH2 gain of function mutations have been reported in approximately 25% of splenic marginal zone lymphomas and are thought to be rare in non-splenic marginal zone lymphomas. These mutations are typically located near the C-terminal PEST domain and lead to protein truncation or, more rarely, are nonsynonymous substitution mutations affecting the extracellular heterodimerization domain. In addition, NOTCH2 PEST domain mutations have been reported in approximately 8% of diffuse large B cell lymphomas and in vitro systems suggest that PEST domain mutant NOTCH2 receptors have increased activity compared to wild type NOTCH2. The prognostic and therapeutic implications of these alterations continue to be elucidated.

Last updated: 2015-12-10 20:45:11 UTC
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Tier 1
MDM2
Variants
MDM2 copy number gain
Primary Sites
Bladder
Tumor Types
Urothelial Carcinoma
Interpretation

MDM2 encodes an E3 ubiquitin ligase that regulates tumor suppressor protein (eg, TP53) turnover through proteasomal degradation. MDM2 overexpression or amplification has been detected in a variety of different cancers including a subset of bladder cancer. Small molecular inhibitors of the MDM2:p53 axis are currently in early phase clinical trials for a number of malignancies.

Last updated: 2016-06-07 02:15:31 UTC
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Tier 2
KLF2
Variants
KLF2 any nonsense
KLF2 any frameshift
KLF2 any missense
Primary Sites
Spleen
Tumor Types
Marginal Zone B Cell Lymphoma
Interpretation

Recurrent inactivating mutations in Kruppel-like factor 2 (KLF2),have been reported in approximately 40% of splenic marginal zone lymphomas (SMZL) but are rarely present in other B-cell lymphomas, according to one study. The majority of KLF2 mutations were frameshift indels or nonsense changes, with missense mutations clustered in the C-terminal zinc finger domains. Functional assays showed that these mutations inactivated the ability of KLF2 to suppress NF-κB activation. IGHV1-2 rearrangement and 7q deletion were primarily seen in SMZL with KLF2 mutation, while MYD88 and TP53 mutations were nearly exclusively found in those without KLF2 mutation. NOTCH2, TRAF3, TNFAIP3 and CARD11 mutations were observed in SMZL both with and without KLF2 mutation. The prognostic and therapeutic implications, if any, of KLF2 alterations in SMZL has yet to be fully elucidated.

Last updated: 2015-12-29 17:07:10 UTC
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Tier 3
JAK3
Variants
JAK3 V722I
Primary Sites
Lung
Thyroid
Colon
Pancreas
Bladder
Tumor Types
Adenocarcinoma
Papillary Carcinoma
Urothelial Carcinoma
Interpretation

JAK3 is a non-receptor protein tyrosine kinase involved in the interferon-alpha/beta/gamma pathway and is a member of the JAK/STAT signaling pathway. The JAK3 V722I variant has been reported as a likely benign germline polymorphism (ClinVar, https://preview.ncbi.nlm.nih.gov/clinvar/variation/134573/) and also as an acquired somatic variant in some tumors. It has been reported to be an activating variant of JAK3 and initial in vitro studies suggest that this variant may play a role in the regulation of PD-L1 expression. Also, V722I resulted in constitutive phosphorylation of Jak3 and was transforming in cell culture. Clinical correlation is recommended.

Last updated: 2019-01-22 19:22:47 UTC
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Tier 2
TP53
Variants
TP53 G245C
TP53 E204*
Primary Sites
Lung
Pancreas
Tumor Types
Adenocarcinoma
Squamous Cell Carcinoma
Interpretation

Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.

Last updated: 2016-06-07 02:09:42 UTC
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Tier 2
TP53
Variants
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.

Last updated: 2016-06-07 02:12:19 UTC
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Tier 2
TP53
Variants
Primary Sites
Colon
Rectum
Appendix
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.

Last updated: 2016-06-07 02:09:01 UTC
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Tier 2
TP53
Variants
Primary Sites
Brain
Tumor Types
Glioblastoma
Interpretation

Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.

Last updated: 2016-06-07 02:10:43 UTC
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Tier 2
KDM5C
Variants
Primary Sites
Kidney
Tumor Types
Clear Cell Renal Cell Carcinoma
Renal Cell Carcinoma
Interpretation

KDM5C (JARID1C) encodes a histone demethylase that is involved in the regulation of transcription and chromatin remodeling. Mutations in KDM5C are noted in about 8% of clear cell renal cancers, and are associated with advanced stage, grade and tumor invasiveness. However, KDM5C- mutated metastatic renal cell cancer are associated with an improved progression free survival in response to sunitinib.

Last updated: 2016-01-20 19:40:49 UTC
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Tier 2
SETD2
Variants
Primary Sites
Kidney
Tumor Types
Clear Cell Renal Cell Carcinoma
Renal Cell Carcinoma
Interpretation

SETD2 protein is a histone H3 lysine 36 trimethylating (H3K36Me3) enzyme affecting chromatin accessibility and DNA methylation. In addition, SETD2 plays an important role in DNA damage repair through promoting homologous recombination, mismatch repair, and activation of p53-mediated checkpoints. SETD2 gene is mutated in 10–15% of ccRCC tumors. Mutational analyses indicate that SETD2 mutations tended to be subclonal, and are thought to be associated with advanced tumor stage at presentation and a higher rate of metastatic disease, as well as decreased survival. Furthermore, SETD2 mutations occur more frequently when PBRM1 is mutated, suggesting that these mutations could be cooperating with each other.

Last updated: 2016-03-08 22:13:23 UTC
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Tier 2
BAP1
Variants
Primary Sites
Kidney
Tumor Types
Clear Cell Renal Cell Carcinoma
Interpretation

BAP1 (BRCA1 associated protein-1) is a histone deubiquitinase, with the ubiquitin C-terminal hydrolase (UCH) domain located at its N-terminal domain. This gene is thought to be a tumor suppressor gene that functions in the BRCA1 growth control pathway. Inactivating mutations of the BAP1 gene have been reported in 10–15% of ccRCCs. In addition to a potentially critical role for BAP1 inactivation in epigenetic deregulation in ccRCC, BAP1 has been found to promote DNA double-strand break repair by homologous recombination, thereby adding to its tumor suppressor function. Multiple studies have revealed that, in a substantial portion of ccRCC tumors with BAP1 mutations, the mutations are subclonal and the protein losses are focal. Interestingly, in ccRCC tumors, the mutations of BAP1 and PBRM1 are largely mutually exclusive. BAP1 protein loss has been associated with advanced clinical stage, higher tumor grade, shorter median survival, worse cancer-specific survival and advanced clinical stage.

Last updated: 2016-01-20 19:32:53 UTC
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Tier 2
PBRM1
Variants
Primary Sites
Kidney
Tumor Types
Clear Cell Renal Cell Carcinoma
Renal Cell Carcinoma
Interpretation

PBRM1 is second most commonly mutated gene (35%) in primary clear cell renal cell carcinoma after VHL. This locus encodes a subunit of ATP-dependent chromatin-remodeling complexes. The encoded protein has been identified as in integral component of complexes necessary for ligand-dependent transcriptional activation by nuclear hormone receptors. PBRM1 is likely a tumor suppressor because the reported mutations are mostly inactivating truncations. PBRM1 mutations, similar to those of VHL, occur early in ccRCC tumorigenesis, with mutations being present in all cancer cells within a tumor in many cases. The contribution of PBRM1 mutations to the clinical outcome of ccRCC patients has been controversial. Some groups reported that these mutations did not seem to correlate with adverse patient survival. However, other groups have reported that PBRM1mutations are positively linked to tumor invasiveness and, based on immunohistochemistry findings, loss of the PBRM1 protein was associated with advanced tumor stage, high Fuhrman grade, and poor overall survival.

Last updated: 2016-01-20 19:38:53 UTC
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Tier 1
VHL
Variants
Primary Sites
Kidney
Tumor Types
Clear Cell Renal Cell Carcinoma
Renal Cell Carcinoma
Interpretation

The Von Hippel-Lindau (vHL) gene may be altered as a somatic (acquired) alteration and/or as a germline alteration associated with a rare autosomal dominant inherited cancer syndrome predisposing to a variety of malignant and benign tumors including clear cell renal cell carcinoma (ccRCC). The protein encoded by this gene is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. Biallelic VHL gene defects (truncation and missense) occur in approximately 75% of ccRCC cases. In addition, approximately 19% of tumors show evidence of inactivation by methylation of the VHL gene promoter. Studies of VHL mutational status as a prognostic marker in advanced sporadic RCC have been inconsistent. However, recent studies with VEGF-inhibitors suggested that loss of function mutations in VHL were associated with treatment response. There are ongoing clinical trials using the current VEGF-tyrosine kinase inhibitors specifically in patients with vHL. Correlation with clinical findings and genetic counseling may be helpful if there is clinical concern for an inherited cancer syndrome. Germline variants are not reported as part of the analysis for the whole exome sequencing assay for tumors.

Last updated: 2016-05-23 18:13:42 UTC
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Tier 3
KDM6A
Variants
Primary Sites
Kidney
Tumor Types
Clear Cell Renal Cell Carcinoma
Renal Cell Carcinoma
Interpretation

KDM6A (UTX) encodes a histone demethylase enzyme. In vitro and in vivo experiments examining KDM6A depletion and overexpression in bladder tumor cells support a role for KDM6A as a suppressor of tumor growth and cell migration. It is found to be mutated at a low frequency in ccRCC tumors (1%). How KDM6A inactivation contributes to ccRCC tumor biology remains to be determined.

Last updated: 2016-01-20 20:00:27 UTC
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Tier 2
PTEN
Variants
Primary Sites
Kidney
Tumor Types
Clear Cell Renal Cell Carcinoma
Renal Cell Carcinoma
Interpretation

PTEN is an obligate haplo-insufficient tumor suppressor gene and is mutated in a large number of cancers. It encodes a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/mTOR signaling pathway. PTEN mutations are loss-of-function mutations and occur in 1% to 5% of ccRCCs. Recent studies suggest that only biallelic loss, resulting from deletion and/or inactivating mutations, is associated with an adverse outcome in ccRCCs. Whether PTEN alterations predict for responsiveness to mTORC1 inhibitors is less certain at this time.

Last updated: 2016-01-20 20:54:58 UTC
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Tier 1
FLCN
Variants
FLCN any mutation
Primary Sites
Kidney
Tumor Types
Renal Cell Carcinoma
Interpretation

FLCN gene mutations cause Birt-Hogg-Dubé (BHD), a hereditary renal cancer syndrome. A classic triad of findings characterizes BHD, which includes cutaneous fibrofolliculomas, pulmonary cysts, and renal tumors. The condition is caused by germline mutations in the FLCN gene, which encodes folliculin; the function of this protein is largely unknown, although FLCN has been linked to the mTOR pathway. Somatic second-hit mutations identified in BHD-associated renal tumours are consistent with a tumour-suppressor function for FLCN. Individuals with BHD have about a 34% lifetime risk for renal cancer, most frequently diagnosed in the fifties. Additionally, male FLCN mutation carriers are twice as likely to be affected as female carriers. Approximately 50% of BHD-related renal tumors manifest as a chromophobe/oncocytic hybrid: 34% chromophobe, 9% clear cell, 5% oncocytoma, and 2% papillary.

Last updated: 2016-01-20 21:20:16 UTC
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Tier 2
FGFR1
Variants
FGFR1 copy number gain
Primary Sites
Pancreas
Tumor Types
Adenocarcinoma
Interpretation

Amplification of FGFR1 has been reported in less than 5% of cases of pancreatic adenocarcinoma. Sequence analysis has demonstrated an activating KRAS mutation (exon 2) in all FGFR1-amplified cases according to one study. In vitro studies suggest that proliferation of a cell line with FGFR1 amplification may be inhibited using the FGFR1 inhibitor BGJ398. In the proper clinical context, FGFR1 may represent a potential new therapeutic target in a subset of patients harbouring FGFR1-amplified tumours, however, further study is required.

Last updated: 2016-01-21 02:20:23 UTC
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Tier 2
SPOP
Variants
Primary Sites
Prostate
Tumor Types
Adenocarcinoma
Interpretation

SPOP (Speckle-type POZ protein) encodes a Cullin 3-based E3-ubiquitin ligase that has several substrates, including the androgen receptor (AR), and steroid receptor coactivator 3 (SRC-3). Upon SPOP mutation in prostate cancer, impaired ubiquitination of its substrates can lead to enhanced AR signaling and cell proliferation. Both AR and AR coactivators are substrates deregulated by SPOP mutation, providing a possible explanation for the associated increase in AR activity seen in this subtype of prostate cancers. SPOP mutations exclusively occur in ETS-negative group of prostate cancer. ERG ubiquitination is also regulated by SPOP. ERG fusion proteins evade SPOP-mediated degradation. This might explain the reason for mutual exclusivity of ETS fusion and SPOP mutation in prostate cancer and create a potential novel therapeutic avenue for ETS fusion tumors. SPOP mutant are significantly associated with CHD1 deletions at 5q21 or 6q21 regions. CHD1 gene controls the transcriptional activity across the genome. It is recurrently deleted in 10%-25% of primary and metastatic prostate cancer, and particularly focal homozygous deletions are restricted to ETS-negative tumors. The SPOP-mutant/CHD1-deleted subset of prostate cancer have characteristic molecular features, including high levels of DNA methylation, homogeneous gene expression patterns, distinct somatic copy-number alterations (SCNA), as well as frequent overexpression of SPINK1 mRNA. The latter is associated with aggressive disease and increased risk of biochemical recurrence. The SPINK1 may act through EGFR pathway, hence, EGFR inhibitors may have therapeutic role in SPINK1-postive prostate cancer.

Last updated: 2016-06-20 19:59:09 UTC
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Tier 2
ERBB2
Variants
ERBB2 V842I
Primary Sites
Colon
Rectum
Pancreas
Tumor Types
Adenocarcinoma
Interpretation

The ERBB2 p.V842I mutation has been previously reported in several cancer types and has been reported to be an activating mutation. The potential for these mutations to be used for selection of patients to targeted therapies continues to be evaluated.

Last updated: 2016-02-22 22:23:50 UTC
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Tier 3
CTNNB1
Variants
CTNNB1 codon(s) 32, 33, 34, 35, 36, 37, 41, 45 any
Primary Sites
Uterus
Tumor Types
Sarcoma
Interpretation

Beta catenin is a transcriptional co-regulator and an adapter protein for cellular adhesion; it comprises part of the Wnt signaling pathway and intracellular levels of beta-catenin are regulated by its phosphorylation, ubiquitination and proteosomal degradation. Accumulation of nuclear beta catenin can lead to a tumoral phenotype and oncogenic transformation in a variety of solid tumors. Various oncogenic mutants of beta catenin have been found in different tumor types which alter its degradation, leading to its accumulation and promoting tumor growth. Mutations in exon 3 of CTNNB1 result in stabilization of a protein that resists degradation, leading to nuclear accumulation of b-catenin, have been described in endometrioid endometrial carcinoma. The reported frequency of CTNNB1 mutations in endometrioid endometrial carcinoma ranges from 14-44%. However, these mutations are not described previously in endometrial sarcomas. Of note, CTNNB1 mutations are highly common in desmoid fibromatosis.

Last updated: 2020-07-24 14:51:24 UTC
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Tier 2
CHD1
Variants
CHD1 any indel
Primary Sites
Prostate
Tumor Types
Adenocarcinoma
Interpretation

CHD1 (chromodomain helicase DNA protein binding domain 1) gene controls the transcriptional activity across the genome. It is recurrently deleted in 10%-25% of primary and metastatic prostate cancer, and particularly focal homozygous deletions are restricted to ETS-negative tumors. CHD1 deletion may contribute to the distinctive patterns of genomic instability observed in CHD1del tumors.The SPOP-mutant/CHD1-deleted subset of prostate cancer have characteristic molecular features, including high levels of DNA methylation, homogeneous gene expression patterns, distinct somatic copy-number alterations (SCNA), as well as frequent overexpression of SPINK1 mRNA.

Last updated: 2016-02-09 20:13:33 UTC
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Tier 2
PTEN
Variants
PTEN any deletion
PTEN any missense
Primary Sites
Prostate
Tumor Types
Adenocarcinoma
Interpretation

PTEN is a tumor suppressor gene, located on chromosome 10q23, and loss of PTEN results in upregulation of the PI3K/ AKT pathway. Loss of PTEN may occur due to homozygous deletion, nonsense mutations, promoter hypermethylation, or with loss of heterozygosity (LOH). In prostate cancer, homozygous deletions spanning the PTEN locus occurs at one of the highest rates of any tumor type studied thus far. PTEN mutations may occur in multiple exons. Approximately in 25%-70% of prostate cancer, PI3K pathway has been altered either through PI3k overactivation or PTEN inactivation. PTEN is inactivated mainly through deletion in nearly 40%, or mutations in about 10%; both are more common in advanced prostate cancer.

Last updated: 2016-01-30 18:37:48 UTC
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Tier 1
ERBB2
Variants
ERBB2 S310F
ERBB2 S310Y
ERBB2 R157W
Primary Sites
Breast
Lung
Bladder
Ureter
Kidney
Tumor Types
Adenocarcinoma
Urothelial Carcinoma
Interpretation

Activating extracellular domain ERBB2 mutations (S310F, S310Y, R157W) have been identified in urothelial carcinoma (enriched in micropapillary variant) and adenocarcinomas of breast and lung. These activating mutations may have therapeutic potential in some clinical settings.

Last updated: 2017-01-20 03:28:23 UTC
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Tier 1
BRAF
Variants
BRAF V600E
BRAF codon(s) 600 any
Primary Sites
Bone
Lung
Bone Marrow
Lymph Node
Skin
Tumor Types
Langerhans Cell Histiocytosis
Histiocytic and Dendritic Cell Neoplasms
Interpretation

B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. Mutations of B-RAF have been described in up to 40-70% of Langerhans cell histiocytosis and approximately 50% of Erdheim-Chester disease. The hotspot for mutations in BRAF is at codon Val600 and these are activating mutations. The most common activating mutation is p.Val600Glu(V600E). Various B-Raf inhibitors(Vemurafenib, Dabrafenib) have been FDA approved for therapy for some tumor types in certain settings, and clinical trials for advanced BRAF V600 mutation-positive tumors using targeted therapy (often in combination with other therapy) may be available (clinical trials.gov).

Last updated: 2018-11-12 20:40:44 UTC
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Tier 2
ERBB2
Variants
ERBB2 exon(s) 20 insertion
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

ERBB2 exon 20 insertions occur within exon 20, which encodes part of the kinase domain. These mutations occur with a frequency of approximately 2--4% of all NSCLC. Overall, in-frame ERRB2 insertions in exon 20 have been reported in approximately 6% of cases of lung adenocarcinoma which are negative for EGFR, KRAS, ALK alterations and these variants are more frequent in patients who were never-smokers. Mutations in ERRB2 do not have an independent prognostic value in lung adenocarcinoma, according to a recent study. In vitro studies have shown that this specific variant is associated with constitutive kinase activation and is associated with sensitivity to some ERBB2 inhibitors and therefore, it may represent a targetable mutation in some clinical settings. Please refer to clinicaltrials.gov for additional information. Recommend correlation with other clinical and laboratory findings.

Last updated: 2018-06-14 19:38:36 UTC
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Tier 2
PTEN
Variants
PTEN any deletion
PTEN G129R
Primary Sites
Brain
Tumor Types
Glioblastoma
Interpretation

PTEN is an obligate haplo-insufficient tumor suppressor gene and is mutated in a large number of cancers. It encodes a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/mTOR signaling pathway. Most PTEN mutations are loss-of-function mutations. Mono-allelic or bi-allelic loss of PTEN is found in a considerable fraction of tumors, including gliomas (75%). In glioblastoma, PTEN loss/deletion is associated with poor patient prognosis, and/or shorter disease-free survival. There are ongoing clinical trials investigating anti-tumor activity of agents in recurrent glioblastoma with this mutation.

Last updated: 2018-06-13 19:01:42 UTC
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Tier 3
PTEN
Variants
PTEN Y68H
Primary Sites
Endometrium
Tumor Types
Adenocarcinoma
Interpretation

PTEN is a tumor suppressor gene, located on chromosome 10q23. It encodes a lipid and protein phosphatase that negatively regulates the PI3K/AKT/mTOR pathway. Cancer-associated alterations in this gene often result in loss of PTEN protein and upregulation of the PI3K/AKT/mTOR pathway. Germline mutations of PTEN lead to inherited hamartoma and Cowden syndrome while somatic mutations are also known to occur in multiple malignancies. PTEN p.Y68H is a reported pathogenic variant that causes tyrosine to histidine substitution at codon 68 affecting NH2-terminal phosphatase domain. This variant has been reported previously in association with PTEN-related disorders. Functional studies demonstrate that individuals harboring this variant have decreased levels of the PTEN protein when compared to wild type controls. However, its clinical significance remains to be fully elucidated.

Last updated: 2016-10-11 21:36:23 UTC
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Tier 2
KRAS
Variants
KRAS Q22K
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

KRAS belongs to the RAS family of oncogenes. KRAS mutations are detected in approximately 20% to 25% of lung adenocarcinoma. Contrary to most other oncogenic driver mutations, KRAS is more often found in smokers and is detected at lower frequency in East Asian patient cohorts. Mutations in KRAS are usually mutually exclusive with other oncogenic driver aberrations including EGFR, BRAF, HER2 mutations and ALK and ROS1 rearrangements. KRAS mutations in NSCLC most often occur in codons 12 or 13 and with a lower frequency in codon 61. KRAS Q22K mutation consists of a C to A transversion substituting lysine for glutamine. This KRAS variant, at codon 22, is exceedingly rare in lung cancers, and also only rarely been described in very few other cancers. Mutations at this site have also been reported as germline mutations in Noonan syndrome. The preclinical studies have shown that cell lines expressing the KRAS Q22K mutation possess high in vivo oncogenic potential, higher than that of wild-type KRAS. The prognostic as well as predictive role of this and other KRAS mutations continues to be studied. Although various attempts inhibiting KRAS have been made, there is no established therapy specific for this large patient subpopulation.

Last updated: 2016-02-11 22:26:32 UTC
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Tier 3
MET
Variants
MET T1010I
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Follicular Carcinoma
Interpretation

The p.T1010I mutation, in the cytoplasmic juxtamembrane domain of MET has been shown to increase growth factor independent proliferation and motility in vitro in tumor cell lines in some studies. This mutation has seen more frequently in thyroid carcinomas than in the goiter controls. But its significance has been challenged by other studies which report a low incidence of T1010I mutation in both tumors and controls and not resulting in an enhanced c-MET phosphorylation. The utility of MET pathway inhibitors also continues to be explored. This variant has also been reported as a germline variant present in less than 1% of the general population. Its role in tumor development and progression continues to be studied. Due to conflicting reports of pathogenicity, this variant best characterized as a variant of uncertain significance (VUS) (https://www.ncbi.nlm.nih.gov/clinvar/variation/41624/).

Last updated: 2018-03-06 17:56:37 UTC
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Tier 3
MET
Variants
MET T1010I
Primary Sites
Brain
Tumor Types
Glioblastoma
Interpretation

MET is frequently overexpressed in glioblastomas (GBM), and some gliomas show hepatocyte growth factor (HGF) autocrine activation of the MET signaling pathway. Several studies have found that HGF and MET are expressed at higher levels in human gliomas than in control brain tissue, and that expression levels correlate with tumor grade. Some studies have shown that the HGF expression in high-grade (WHO Grade III-IV) tumors was significantly higher than in low-grade (WHO I-II) tumors. Similarly, coexpression of HGF and MET is observed more frequently in Grade IV GBM than in low-grade glioma, consistent with the contribution of an HGF/MET autocrine loop to malignant progression in these tumors. However, MET sequence alterations have been rare. The p.T1010I mutation, in the cytoplasmic juxtamembrane domain of MET has been reported in some tumor types and also has been reported as a germline variant present in less than 1% of the general population. Its role in tumor development and progression continues to be studied. The utility of MET pathway inhibitors also continues to be explored.

Last updated: 2020-07-24 14:51:29 UTC
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Tier 1
BRAF
Variants
BRAF T599_V600insV
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Interpretation

This mutation, namely a 1795GTT insertion, results in BRAF V599Ins. Kinase assays on BRAF V599Ins and BRAF V600E show increased enzymatic activity, increased phosphorylation of MEK, MAPK and RSK and a high transformation rate in the cells compared to wild type BRAF. Thus, BRAF V599Ins, similar to BRAF V600E, is a 'gain of function' mutation, with constitutive activation, which accounts for its role in papillary cancer of the thyroid.

Last updated: 2016-06-07 02:19:43 UTC
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Tier 3
FGFR3
Variants
Primary Sites
Brain
Tumor Types
Interpretation

FGFR3 is one of 4 high affinity tyrosine kinase receptors for the fibroblast growth factor family of ligands. On ligand stimulation, FGFR3 undergoes dimerization and tyrosine autophosphorylation, resulting in cell proliferation or differentiation, depending on the cell context, through the mitogen-activated protein kinase (MAPK) and phospholipase Cγ signal transduction pathways. All known mutations are believed to result in ligand-independent activation of the receptor. Germ line mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. However, somatic mutations of FGFR3 gene are very rare in brain tumors. In some cases, the possibility of FGFR3 variants being germline can not be excluded. Clinical correlation is recommended.

Last updated: 2016-02-11 22:33:33 UTC
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Tier 2
KRAS
Variants
KRAS codon(s) 12, 13, 61, 117, 146 any
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Follicular Carcinoma
Interpretation

RAS mutations (HRAS, NRAS and KRAS) are found in all epithelial thyroid malignancies. The frequency of KRAS mutations in thyroid carcinomas is 2-3%. Overall, RAS mutations are identified in 10--20% of papillary carcinomas (follicular variant), 40--50% of follicular carcinomas and 20--40% of poorly differentiated and anaplastic carcinomas. Of note, RAS point mutations are mutually exclusive with other thyroid mutations such as BRAF, RET/PTC, or TRK rearrangements in papillary thyroid cancers. In follicular carcinomas, RAS mutations are mutually exclusive with PAX8-PPARG rearrangements. RAS mutations have also been associated with more aggressive disease and distant metastasis. The therapeutic implications of RAS mutations in thyroid cancer are unknown at this time.

Last updated: 2019-01-22 19:27:00 UTC
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Tier 3
APC
Variants
Primary Sites
Brain
Tumor Types
Glioblastoma
Interpretation

The APC gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. APC promotes rapid degradation of beta-catenin and participates in Wnt signaling as a negative regulator. APC is also involved in other processes including cell migration, cell adhesion, transcriptional activation and apoptosis. Germline defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. Somatic mutations in this gene may be observed in colorectal cancer (CRC), stomach cancer and desmoid tumors. Although APC mutations have been reported in up to 5% of low grade gliomas and up to 13% primary glioblastomas (GBM), evidence regarding their involvement in CNS tumors is still limited. Further studies are needed to explore the clinical value of these mutations in CNS tumors.

Last updated: 2016-02-11 22:36:11 UTC
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Tier 2
GNAS
Variants
GNAS Q227L
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

This GNAS mutation causes constitutive activation of the G-protein complex and activates adenylate cyclase to produce cyclic-AMP (cAMP) that can activate oncogenic pathways. The frequency of GNAS mutation in non-small cell carcinoma of the lung cases is relatively low (<5%) and its significance remains to be fully elucidated.

Last updated: 2016-02-12 20:40:08 UTC
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Tier 2
KRAS
Variants
KRAS G12A
KRAS G12V
KRAS G12D
KRAS G12S
KRAS G12R
Primary Sites
Ovary
Tumor Types
Adenocarcinoma
Interpretation

KRAS mutations have been reported to be present in 16 to 41% of cases of low grade serous carcinoma of the ovary. The prognostic significance of KRAS mutations in ovarian tumors is uncertain; some reports suggest that patients with KRAS G12V may have shorter overall survival than patients without mutation, while other reports suggest that KRAS mutations in some low grade carcinomas of the ovary may be associated with slightly improved prognosis. In-vitro studies showed that cell lines with KRAS G12V mutation are more sensitive to selumetinib (MEK inhibitor) compared to cells with KRAS G12D. The clinical response to MEK inhibitors in patients with these tumors and mutations remains to be elucidated.

Last updated: 2016-02-12 21:08:04 UTC
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Tier 1
DNAJB1
Variants
DNAJB1-PRKACA rearrangement
Primary Sites
Liver
Tumor Types
Hepatocellular Carcinoma
Interpretation

The DNAJB1-PRKACA fusion transcript is detected in 80 to 100% of fibrolamellar hepatocellular carcinomas. Detection of DNAJB1-PRKACA is thought to be a very sensitive and specific finding in support of the diagnosis of fibrolamellar carcinoma, and may contribute to tumor pathogenesis. The therapeutic targetability of this alteration remains to be elucidated.

Last updated: 2016-02-12 21:25:57 UTC
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Tier 1
NCOA2
Variants
NCOA2 copy number gain
Primary Sites
Prostate
Tumor Types
Adenocarcinoma
Interpretation

The nuclear receptor coactivator NCOA2 was identified as a highly significant target gene on the 8q13 amplicon and is also subject to mutation in some tumors lacking gene amplification. Copy number gains or mutations in NCOA2 and other regulators of nuclear receptor function such as NCOA2 are present in primary tumors, thereby extending the potential importance of AR pathway perturbation to disease initiation. The frequency of NCOA2 alteration could be as high as 20 and 63 percent in primary and metastatic tumors respectively. The genomic and functional data suggest that NCOA2 functions as a driver oncogene in primary tumors by increasing AR signaling, which is known to play a critical role in early and late stage prostate cancer. This may be a potentially targettable pathway alteration in some settings.

Last updated: 2016-02-12 21:35:20 UTC
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Tier 1
AR
Variants
AR copy number gain
Primary Sites
Prostate
Tumor Types
Adenocarcinoma
Small Cell Carcinoma
Interpretation

The androgen receptor (AR) is a ligand-dependent nuclear transcription factor. The AR gene undergoes multiple alterations leading to increased activity in prostate cancer, including gene amplification, point mutations, and alteration in splicing leading to constitutively active variants. However, these alterations take place largely, if not exclusively, in metastatic, castration resistant prostate cancer (CRPC). It is believed that lesions in the AR gene itself do not play a role in the pathogenesis of prostate cancer, but instead emerge during treatment as a mechanism of resistance to therapies targeting the androgen axis. Even in advanced cancers that no longer respond to androgen deprivation therapy, accumulating evidence has shown that AR signaling remains active and plays a critical role in disease progression. Androgen receptor activity, as inferred by the induction of AR target genes, was significantly increased in SPOP and FOXA1 mutant tumors when compared to normal prostate or ERG-positive tumors.

Last updated: 2017-01-20 03:28:39 UTC
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Tier 2
TP53
Variants
TP53 copy number loss
TP53 any deletion
Primary Sites
Prostate
Tumor Types
Adenocarcinoma
Interpretation

P53 activates the transcription of genes involved in cell cycle arrest, DNA repair, and apoptosis. Deletion and point mutation at the TP53 locus occur in 25%-40% and 5%-40% of prostate cancer, respectively. Although the frequency of p53 mutations seems to be lower in prostate cancer than in other cancers, these alterations are not exclusively late events, as they have been shown in 25% to 30% of clinically localized prostate cancer. Several studies indicate that p53 overexpression may be associated with poor prognosis, especially when present in combination with Bcl2. Interestingly, SPOP mutations are also mutually exclusive with deletions and mutations in the TP53 tumor suppressor.

Last updated: 2016-06-07 02:20:55 UTC
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Tier 2
ERG
Variants
ERG-TMPRSS2 rearrangement
Primary Sites
Prostate
Tumor Types
Adenocarcinoma
Carcinoma
Interpretation

Approximately half of all prostate cancers harbor recurrent gene fusions involving ETS transcription factors. The most common gene rearrangement is the fusion of the 5' untranslated region of TMPRSS2 (an androgen-regulated gene) and ERG (a member of ETS transcription factor family). TMPRSS2:ERG fusion is cancer-specific and results in ERG protein overexpression. ERG fusion is associated with adverse clinicopathologic predictors, metastases, and disease-specific death in non-PSA screened populations. In a cohort of active surveillance patients, it is correlated with increased tumor volume and higher Gleason grade. The effect of ERG fusions on aggressive features or outcome following radical prostatectomy is less clear and needs further elucidation.

Last updated: 2022-08-29 14:54:13 UTC
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Tier 1
EGFR
Variants
EGFR copy number gain
Primary Sites
Bladder
Tumor Types
Urothelial Carcinoma
Interpretation

EGFR has been reported to show increased expression in a subset of bladder cancers and may be a targetable alteration in some clinical settings.

Last updated: 2016-02-18 04:07:15 UTC
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Tier 1
AR
Variants
AR T878A
AR H875Y
Primary Sites
Prostate
Tumor Types
Adenocarcinoma
Interpretation

Mutations in the Androgen Receptor are rare in untreated prostate cancer and have been described in 15-33% of castration resistant prostate cancer and hormone refractory tumors. Among these, the H875Y and T878A are recurrent mutations that have been previously described. These mutations alter responses to androgen receptor antagonists. Cases with two such mutations have been previously reported and the mutations may co-exist on the same allele.

Last updated: 2016-02-28 00:00:36 UTC
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Tier 3
IRS2
Variants
IRS2 copy number gain
Primary Sites
Colon
Gall Bladder
Brain
Tumor Types
Adenocarcinoma
Cholangiocarcinoma
Glioblastoma
Interpretation

IRS1 and IRS2 are the key protein effectors for transmitting insulin signals from the insulin-like growth factor receptor to the nucleus via the PI3K / AKT / mTOR pathway. IRS2 has been previously noted to be recurrently focally amplified in several anecdotal studies across multiple cancer types (colorectal cancer PMID: 23594372, cholangiocarcinoma PMID:26684807, glioblastoma PMID: 14655756, rhabdomyosarcoma PMID: 23578105), suggesting that this could be a "driver" alteration in a subset of cancer.. IRS2 amplifications have also been associated with sensitivity to the insulin receptor inhibitor BMS-754807 in colorectal cancer cell lines (PMID: 25527633). There is no direct evidence to connect IRS2 amplification status with sensitivity to any targeted therapy regimen in patients; however, an attractive hypothesis is that tumors harboring IRS2 amplifications could be sensitive to drugs targeting insulin signaling, PI3K, AKT, and mTOR. Drug sensitivity and exome sequencing data from colorectal patient derived tumor xenografts have associated IRS2 copy gains with sensitivity to anti-EGFR therapies (PMID: 26416732).

Last updated: 2016-04-05 17:02:32 UTC
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Tier 3
SMAD4
Variants
SMAD4 C324Y
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Follicular Carcinoma
Interpretation

Smad4 is tumor suppressor gene and is crucial for thyroid development and function. It is key component of the transforming growth factor beta (TGFB) pathway which regulates the expression of thyroid-specific genes. The role of SMAD4 in thyroid tumorigenesis remains unclear. However, mutations affecting the coding region of the SMAD4 gene have been detected in some sporadic thyroid neoplasms. Studies that analyzed expression of SMAD4 in thyroid tumors gave contradictory results. Some studies showed that the expression of SMAD4 was reduced in thyroid cancer cells. Other studies indicated that it was expressed and present in the nucleus in all thyroid cell lines and controls analyzed, indicating propagation of TGFB signaling in thyroid tumors. Of note, a SMAD4 mutation C324Y, recently isolated from nodal metastases of papillary thyroid carcinoma (PTC), was confirmed to cause an increase in TGFB signaling and lead to the acquisition of transformed phenotype and invasive behavior in thyroid cells, enabling them to proliferate independently from thyroid-stimulating hormone.

Last updated: 2016-03-09 16:00:04 UTC
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Tier 3
FGFR3
Variants
Primary Sites
Thymus
Tumor Types
Thymic Carcinoma
Interpretation

FGFR3 is one of 4 high affinity tyrosine kinase receptors for the fibroblast growth factor family of ligands. On ligand stimulation, FGFR3 undergoes dimerization and tyrosine autophosphorylation, resulting in cell proliferation or differentiation, depending on the cell context, through the mitogen-activated protein kinase (MAPK) and phospholipase Cγ signal transduction pathways. Some FGFR3 mutations are believed to result in ligand-independent activation of the receptor. Somatic mutations of FGFR3 gene are not reported in thymic tumors. However, in some cases, the possibility of FGFR3 variants being germline can not be excluded. Clinical correlation is recommended.

Last updated: 2016-03-09 16:02:30 UTC
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Tier 2
CDKN2A
Variants
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Squamous Cell Carcinoma
Interpretation

CDKN2A gene functions as an important tumour suppressor in various human malignancies including colorectal cancer, and its activation prevents carcinogenesis via induction of cell growth arrest and senescence. Majority of the CDKN2A mutations span exon 2 and result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. Somatic mutations of CDKN2A are present in various tumor types but have not been well characterized in colorectal cancer. However, epigenetic silencing of CDKN2A by hypermethylation has been reported be a possible predictive factor of poor prognosis in patients with colorectal cancer.

Last updated: 2016-11-04 00:48:03 UTC
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Tier 2
KRAS
Variants
KRAS codon(s) 12, 13, 61, 117, 146 any
Primary Sites
Appendix
Tumor Types
Adenocarcinoma
Interpretation

KRAS is a gene that encodes one of the several proteins in the epidermal growth factor receptor (EGFR) signaling pathway that is important in the development and progression of cancer. KRAS can harbor oncogenic mutations that yield a constitutively active protein. KRAS mutations are frequent in low-grade mucinous tumors of appendiceal origin and pseudomyxoma peritonei (43-100%) where mutations commonly occur in codon 12 or 13, with G12D and G12V being the most common. However, appendiceal adenocarcinoma cases with goblet cell features usually lack KRAS mutations. Mutations in the KRAS gene may indicate poor prognosis and drug response with therapies targeted to EGFR in some settings. However, this should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2018-03-06 17:57:05 UTC
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Tier 2
TP53
Variants
Primary Sites
Skin
Tumor Types
Langerhans Cell Histiocytosis
Interpretation

Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.

Last updated: 2016-06-07 02:11:27 UTC
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Tier 2
PDGFA
Variants
PDGFA Y273F
Primary Sites
Breast
Tumor Types
Ductal Carcinoma
Interpretation

Although PDGFRA activating mutations in patients with GIST, primarily D842V, were reported to be associated with resistance to the tyrosine kinase inhibitor, Imatinib; however, PDGFRA mutations in breast cancer are very rare. Moreover, this specific missense mutation in the extracellular domain of PDGFRA, has not been reported and its clinical significance is unknown.

Last updated: 2016-03-11 19:56:38 UTC
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Tier 2
NKX2-1
Variants
NKX2-1 copy number gain
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

NKX2-1 is a lineage-specific transcription factor that is frequently focally amplified in lung adenocarcinoma (PMID 17982442). NKX2-1 amplification supports a diagnosis of lung adenocarcinoma, as this event occurs rarely in other tumor types, including in lung squamous or small-cell lung cancer. NKX2-1 has been proposed to be an oncogenic "survival factor" for lung adenocarcinomas (PMID 23763999) though studies have also demonstrated tumor suppressor effects for this gene (PMID 21471965). There is no known relationship between NKX2-1 amplification and drug sensitivity.

Last updated: 2016-03-17 01:56:18 UTC
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Tier 2
KRAS
Variants
Primary Sites
Ampulla (Pancreaticobiliary Duct)
Pancreas
Tumor Types
Interpretation

KRAS is a gene that encodes one of the several proteins in the epidermal growth factor receptor (EGFR) signaling pathway that is important in the development and progression of cancer. KRAS can harbor oncogenic mutations that yield a constitutively active protein. The frequency of the KRAS gene mutations in intraductal papillary mucinous neoplasms (IPMNs) varies from 38.2% to 100%. There appears to be no significant difference among the incidence of KRAS mutation in the various grades of dysplasia: 87% in low-grade, 90.2% in intermediate grade and 70.7% in high-grade dysplasia. This mutation is considered to be an early event in the neoplastic transformation of IPMNs. KRAS mutations have the highest frequency in the pancreatobiliary subtype (100%) and the lowest frequency in the intestinal subtype (46.2%). Studies demonstrate that KRAS mutations in different tumors may have various biological, prognostic, and possibly therapeutic implications in some settings.

Last updated: 2016-03-18 21:03:01 UTC
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Tier 2
FGFR2
Variants
FGFR2 P253R
Primary Sites
Breast
Tumor Types
Invasive Ductal Carcinoma
Lobular Carcinoma
Interpretation

The receptor tyrosine kinase FGFR2 is one of four fibroblast growth factor receptors designated FGFR1-4 that activate FGF signalling upon trans-autophosphorylation of the receptor dimers. Some genetic alterations of FGFR2 lead to aberrant activation of FGFR2 signaling cascades due to the creation of autocrine signaling loop or the release of FGFR2 from autoinhibition. It is known that some FGFR2 gene variations including intronic polymorphisms confer a risk for breast cancer, preferentially for estrogen receptor-positive breast tumors. FGFR2 and FGF10, the main ligand of FGFR2, are both overexpressed in 5-10% of breast tumors. Somatic missense mutations have also been reported in breast cancer leading to ligand independent activation of FGFR2. In cell line and xenograft experiments, inhibition/knockdown of FGFR2 results in anti-tumour effects, suggesting the oncogenic role of FGFR2, raising the potential of FGFR2 as a target of therapy in FGFR2 driven cancers. The P253R variant in FGFR2 has also been described in some constitutional disorders including craniosynostosis syndromes (eg, Apert syndrome).

Last updated: 2020-07-24 14:52:51 UTC
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Tier 2
KRAS
Variants
Primary Sites
Bladder
Tumor Types
Urothelial Carcinoma
Interpretation

KRAS is a gene that encodes one of the several proteins in the growth factor signaling pathway(s) and is important in the development and progression of a variety of cancers. KRAS can harbor oncogenic mutations that yield a constitutively active protein. The frequency of the KRAS gene mutations in urothelial carcinoma of urinary bladder is very low (3% to 7%), and these mutations occur in all stages and grades. In the context of bladder tumors, mutations in the KRAS gene do not appear to be predictors for recurrence-free, progression-free and disease-specific survival according to some studies.

Last updated: 2016-03-29 19:28:17 UTC
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Tier 3
FGFR3
Variants
FGFR3 F384L
Primary Sites
Lung
Breast
Colon
Pancreas
Thyroid
Liver
Tumor Types
Adenocarcinoma
Carcinoma
Squamous Cell Carcinoma
Papillary Carcinoma
Follicular Carcinoma
Interpretation

FGFR3 is one of 4 high affinity tyrosine kinase receptors for the fibroblast growth factor family of ligands. On ligand stimulation, FGFR3 undergoes dimerization and tyrosine autophosphorylation, resulting in cell proliferation or differentiation, , through the mitogen-activated protein kinase (MAPK) and phospholipase Cg signal transduction pathways. Some FGFR3 mutations are believed to result in ligand-independent activation of the receptor. However, FGFR3 F384L mutation is not associated with activation of FGFR and, in NIH-3T3 cells, it was demonstrated to be devoid of any transforming activity. In some cases, the possibility of FGFR3 variants being of germline origin, cannot be excluded. The FGFR3 F384L mutation has been reported as a benign/likely benign germline variant in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/134404/). Clinical correlation is recommended.

Last updated: 2019-02-22 18:08:17 UTC
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Tier 2
SEPT14
Variants
SEPT14 copy number gain
Primary Sites
Brain, Supratentorial
Tumor Types
Glioblastoma
Interpretation

The SEPT14 gene has been described as a fusion partner with EGFR in up to 4% of glioblastomas. In that context, glioma cell lines harboring this gene fusion were found to be susceptible to EGFR inhibitors in vitro. The functional significance of an isolated partial amplification of this gene would be of uncertain significance. Detection of rearrangement of this locus with a fusion partner such as EGFR would require an alternative methodology such as RNAseq or FISH analysis.

Last updated: 2016-03-31 14:04:37 UTC
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Tier 2
CDKN2A
Variants
CDKN2A copy number loss
Primary Sites
Brain
Tumor Types
Glioblastoma
Interpretation

The CDKN2A gene locus is altered in up to approximately 57% of glioblastoma, most commonly as a homozygous deletion, and frequently with concurrent deletion of the CDKN2B locus. CDKN2A/CDKN2B loss may be associated with increased sensitivity to CDK4/6 inhibitors. The efficacy and toxicity profiles of these inhibitors in the context of a variety of cancer types are currently under evaluation in clinical trials.

Last updated: 2019-04-26 15:04:50 UTC
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Tier 1
CDKN2B
Variants
CDKN2B copy number loss
Primary Sites
Brain
Tumor Types
Glioblastoma
Interpretation

The CDKN2B gene locus is altered in up to approximately 55% of glioblastoma, most commonly as a homozygous deletion, and frequently with concurrent deletion of the CDKN2A locus. CDKN2A/CDKN2B loss may be associated with increased sensitivity to CDK4/6 inhibitors. The efficacy and toxicity profiles of these inhibitors in the context of a variety of cancer types are currently under evaluation in clinical trials.

Last updated: 2016-03-31 18:17:27 UTC
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Tier 1
FGFR1
Variants
FGFR1 copy number gain
Primary Sites
Breast
Tumor Types
Invasive Ductal Carcinoma
Interpretation

Amplification of FGFR1 has been reported in approximately 10% of breast cancer and may be associated with adverse outcome according to some reports. It has been reported to be associated with increased expression of FGFR1 and increased activity of downstream growth signaling pathways. Some reports suggest FGFR1 may have a role in regulating response to endocrine therapy. FGFR1 amplification may be a targetable alteration in some clinical settings (PubMed IDs: 20179196, 25400686).

Last updated: 2016-04-09 18:01:57 UTC
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Tier 1
BRAF
Variants
BRAF K601E
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Follicular Carcinoma
Interpretation

B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. Eighty percent of all thyroid cancers are papillary thyroid carcinomas (PTCs). Presence of a BRAF p.Val600Glu (V600E) mutation is highly specific for papillary thyroid carcinoma and is only rarely associated with the follicular variant PTC and other well-differentiated thyroid neoplasms or nodular goiters. The K601E mutation results in an amino acid substitution at position 601 in BRAF, occurring within the highly conserved motif of the kinase domain. This is the second most common BRAF mutation found in thyroid nodules after V600E. Unlike BRAF V600E, K601E is strongly associated with follicular-patterned cancer, particularly with the encapsulated follicular variant of PTC, and may also be found in follicular thyroid carcinomas. Overall, BRAF K601E mutant tumors may show better clinical outcomes than BRAF V600E positive tumors.

Last updated: 2016-04-17 17:35:27 UTC
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Tier 3
BRAF
Variants
BRAF F595S
Primary Sites
Brain
Tumor Types
Medulloblastoma
Interpretation

B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. BRAF mutations are common in a wide spectrum of brain tumors but they are not described in medulloblastomas to our knowledge. BRAF F595 mutations are pathogenic in some tumor types but their clinical significance in medulloblastomas remains to be studied. Various B-Raf inhibitors(Vemurafenib, Dabrafenib) have been FDA approved for therapy for some BRAF mutations in select tumor types in certain settings.

Last updated: 2016-04-17 17:38:32 UTC
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Tier 2
PIK3CA
Variants
Primary Sites
Brain
Tumor Types
Medulloblastoma
Interpretation

PIK3CA mutations have been identified in pediatric and adult gliomas including: anaplastic oligodendrogliomas, anaplastic astrocytomas, glioblastoma multiforme, rosette forming glioneuronal tumors and medulloblastomas. Although PIK3CA mutations are reported in medulloblastoma, their role in tumorigenesis remains controversial. According to some preclinical studies, mutations in PIK3CA likely activate the AKT pathway to progress, rather than initiate, WNT-medulloblastoma. PIK3CA mutations are potentially targetable in some settings and pathway inhibitors are currently under investigation.

Last updated: 2016-04-17 17:39:22 UTC
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Tier 3
PTPN11
Variants
Primary Sites
Brain
Tumor Types
Glioblastoma
Interpretation

The PTPN11gene encodes SHP-2, a widely expressed cytoplasmic protein tyrosine phosphatase. SHP-2 is essential for activation of the RAS/MAPK signaling cascade. Most mutations are gain-of-function and result in prolonged ligand-dependent activation of the RAS/MAPK cascade. Germ-line PTPN11 mutations cause Noonan syndrome, a developmental disorder characterized by an increased risk of malignancies. Activating somatic mutations in PTPN11 have been documented in certain hematologic malignancies but they are infrequent in solid tumors. According to TCGA data base, about 2% of all the glial tumors harbor somatic mutations in PTPN11 gene but their prognostic and therapeutic significance remains to be fully elucidated. The utility of SHP2 inhibitors continues to be explored in some preclinical studies.

Last updated: 2016-04-17 17:40:01 UTC
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Tier 3
APC
Variants
Primary Sites
Prostate
Tumor Types
Adenocarcinoma
Interpretation

The APC gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. APC promotes rapid degradation of beta-catenin and participates in Wnt signaling as a negative regulator. APC is also involved in other processes including cell migration, cell adhesion, transcriptional activation and apoptosis. Disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. APC mutations have been reported in 3-10% of prostate cancers. In some studies, a high-level of APC promoter methylation was shown to be an independent predictor of a poor prognosis in prostate cancers. However, further studies are needed to explore the clinical value of APC mutations in these tumors.

Last updated: 2016-04-17 17:40:57 UTC
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Tier 2
KRAS
Variants
KRAS codon(s) 12, 13, 61, 117, 146 any
Primary Sites
Ampulla (Pancreaticobiliary Duct)
Liver
Tumor Types
Adenocarcinoma
Cholangiocarcinoma
Interpretation

KRAS is a gene that encodes one of the several proteins in the epidermal growth factor receptor (EGFR) signaling pathway that is important in the development and progression of cancer. KRAS can harbor oncogenic mutations that yield a constitutively active protein. KRAS mutations are common in both extrahepatic (40-49%) and intrahepatic (24-27%) cholangiocarcinomas. Mutations in the KRAS gene may indicate poor prognosis and drug response with therapies targeted to EGFR in some settings. Of note, RAS mutations sensitize tumors to MEK inhibitors. However, this should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2018-06-13 18:58:46 UTC
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Tier 2
CDKN2A
Variants
Primary Sites
Liver
Ampulla (Pancreaticobiliary Duct)
Tumor Types
Cholangiocarcinoma
Adenocarcinoma
Interpretation

CDKN2A gene functions as an important tumor suppressor in various human malignancies including cholangiocarcinomas, and its activation prevents carcinogenesis via induction of cell growth arrest and senescence. Majority of the CDKN2A mutations span exon 2 and result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. Somatic mutations of CDKN2A are present in various tumor types including cholangiocarcinomas where they appear to be more common in extrahepatic cholangiocarcinomas (up to 15%) than in intrahepatic ones. However, epigenetic silencing of CDKN2A by hypermethylation is more frequent, and the frequency ranges from 17% to 83% in different studies. Of note, inactivation of CDKN2A may portend poor clinical outcome according to some studies. However, correlation with other clinical and lab findings is necessary.

Last updated: 2016-11-04 00:47:49 UTC
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Tier 2
CTNNB1
Variants
CTNNB1 codon(s) 41, 45 any
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

Beta catenin is a transcriptional co-regulator and an adapter protein for cellular adhesion; it comprises part of the Wnt signaling pathway and intracellular levels of beta-catenin are regulated by its phosphorylation, ubiquitination and proteosomal degradation. Accumulation of nuclear beta catenin can lead to a tumoral phenotype and oncogenic transformation in a variety of solid tumors. Various oncogenic mutants of beta catenin have been found in different tumor types which alter its degradation, leading to its accumulation and promoting tumor growth. CTNNB1 mutations are particularly common in colorectal carcinomas associated with hereditary non-polyposis colon cancer syndrome and wild type APC gene, and are extremely rare in sporadic colorectal cancers. These mutations consist almost entirely of transitions at codons 41 and 45, and result in stabilization of a protein that resists degradation, leading to nuclear accumulation of β-catenin. Up to 50% of primary colorectal carcinomas with CTNNB1 mutations exhibit microsatellite instability, suggesting that CTNNB1 mutations may be more common in the DNA mismatch repair pathway of tumorigenesis. Microsatellite instability is generally associated with better prognosis when compared to patients with intact mismatch repair pathways. Preclinical studies suggest that CTNNB1 mutations may confer resistance to PI3K-AKT inhibitors in colorectal cancer.

Last updated: 2016-05-04 16:10:00 UTC
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Tier 2
PTEN
Variants
PTEN G165R
Primary Sites
Parathyroid
Tumor Types
Carcinoma
Interpretation

PTEN is a tumor suppressor gene, located on chromosome 10q23. It encodes a lipid and protein phosphatase that negatively regulates the PI3K/AKT/mTOR pathway. Cancer-associated alterations in this gene often result in loss of PTEN protein and upregulation of the PI3K/AKT/mTOR pathway. Germline mutations of PTEN lead to inherited hamartoma and Cowden syndrome while somatic mutations are also known to occur in multiple malignancies. PTEN alterations are rare and not well characterized in parathyroid tumors. One study reported loss of heterozygosity of PTEN in 7 of 14 parathyroid carcinomas. PTEN p.G165R variant is a reported pathogenic variant that causes glycine to arginine substitution at codon 165 affecting NH2-terminal phosphatase domain. This variant has been reported previously in endometrial and CNS tumors in COSMIC data base. Functional studies demonstrate that individuals harboring this variant have decreased levels of the functional PTEN protein when compared to wild type controls. However, its clinical significance remains to be fully elucidated.

Last updated: 2016-05-05 13:20:17 UTC
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Tier 3
CTNNB1
Variants
Primary Sites
Prostate
Tumor Types
Adenocarcinoma
Interpretation

Beta catenin is a transcriptional co-regulator and an adapter protein for cellular adhesion; it comprises part of the Wnt signaling pathway and intracellular levels of beta-catenin are regulated by its phosphorylation, ubiquitination and proteosomal degradation. Accumulation of nuclear beta catenin can lead to a tumoral phenotype and oncogenic transformation in a variety of solid tumors. Various oncogenic mutants of beta catenin have been found in different tumor types which alter its degradation, leading to its accumulation and promoting tumor growth. CTNNB1 mutations in prostate cancer occur rarely, in only 2-5% of cases. Currently, the function of β-Catenin in human prostate cancer continues to be explored. In the context of prostate, β-Catenin may modulate the androgen receptor (AR) pathway. Some preclinical mouse studies have shown that increased β-Catenin levels can cooperate with PTEN loss to promote the progression of aggressive invasive prostate cancer together with squamous metaplasia. Clinical correlation is recommended.

Last updated: 2016-05-05 13:29:28 UTC
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Tier 1
EGFR
Variants
EGFR S768I
EGFR G724S
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Squamous Cell Carcinoma
Interpretation

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR tyrosine kinase inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. EGFR S768I (exon 20) occurs in 1–2% of EGFR mutant lung cancers and is often coincident with other EGFR mutations. EGFR S768I is reported to be sensitive to EGFR-TKIs. EGFR G724S (exon 18) is very rare and its significance is unknown.

Last updated: 2016-05-05 13:32:06 UTC
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Tier 2
EGFR
Variants
EGFR R776H
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

The epidermal growth factor receptor (EGFR) is a cell surface receptor belonging to the ErbB family tyrosine kinase receptors. EGFR is involved in cell growth control through its role in the two main intracellular pathways, the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase- (PI3K-) protein kinase B (AKT) pathway. The over-expression or mutation of EGFR may be responsible for the constitutive activation of these pathways. In the colorectal cancer, the EGFR has been found to be frequently over expressed, and may be associated with tumor stage and prognosis. In a subset of such patients, the addition of anti-EGFR monoclonal antibodies to the conventional chemotherapeutic regimens may expand response rates and increase progression-free survival. Somatic EGFR mutations are infrequent in colorectal cancers. The frequency varies from 0.34 to 3.3% in Western population, and from 12% to 22.4% in Asians. R776H is a recurrent mutation in the hinge region of the kinase domain and is known to activate EGFR in a ligand independent manner. In some cases, the possibility of R776H variant being of germline origin, cannot be excluded. The clinicopathologic correlation of EGFR mutations in colorectal cancers continues to be explored.

Last updated: 2016-05-05 13:40:13 UTC
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Tier 2
KIT
Variants
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

c-kit (CD117) is a growth factor receptor of the tyrosine kinase subclass III family, normally expressed in a variety of human tissues. Gain-of-function mutations of the c-kit gene have been identified that produce ligand-independent activation of c-kit and cell proliferation. Some of these mutations appear causative in the pathogenesis of adult mastocytosis and most gastrointestinal stromal tumors (GISTs). c-kit receptor and its ligand have been demonstrated in human colon cancer cell lines. Some studies have shown high frequency of c-Kit overexpression in stage II colon cancer patients (59.3%) with significant correlation between c-Kit overexpression and reduced disease free survival. However, other studies failed to demonstrate c-kit expression in a significant number of colorectal cancers suggesting that c-kit kinase activation is not a prominent pathogenetic feature of colorectal cancers. Role of c-Kit continues to be studied in colon cancers.

Last updated: 2016-05-05 13:42:01 UTC
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Tier 2
GNAS
Variants
GNAS codon(s) 201, 844 any
Primary Sites
Pancreas
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations in GNAS are frequently found in intraductal papillary mucinous neoplasms (IPMNs) of pancreas, and have been identified in 41% to 66% of cases. All of these mutations involved codon 201 (R201C or R201H). However, the GNAS mutation was infrequent in typical pancreatic ductal adenocarcinomas (PDAs). These mutations are lead to disruption of the intrinsic hydrolytic activity of Gsα, leading to constitutive activation. GNAS mutations seem to be an early event in IPMN development. The clinical significance of these mutations remains to be established.

Last updated: 2016-06-07 02:23:28 UTC
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Tier 1
ALK
Variants
ALK R1275Q
Primary Sites
Soft Tissue
Brain
Brain, Infratentorial
Brain, Supratentorial
Tumor Types
Neuroblastoma
Interpretation

The anaplastic lymphoma kinase (ALK) has emerged as a potentially relevant biomarker and therapeutic target in pediatric solid and hematologic malignancies. It is a receptor tyrosine kinase (RTK) that is known to be activated either by point mutations or by chromosomal translocations. These genetic alterations act as oncogenic drivers and promote constitutive, ligand-independent activation of this RTK. Recurrent activating point mutations are seen within kinase domain in both the hereditary and sporadic form of neuroblastoma cases (7-10%). According to some studies, the presence of an ALK aberration could be a biomarker of aggressive disease and inferior clinical outcome. Clinical trials of crizotinib in neuroblastoma are underway. The R1275Q mutation is most common variant among ALK-mutated neuroblastomas (33%), and is found in both sporadic and familial cases. The R1275 amino acid substitution lies within the activation loop and causes constitutive ligand-independent activation of this RTK. Both preclinical and clinical studies suggest that this mutation could be sensitive to ALK inhibition.

Last updated: 2016-10-11 21:43:00 UTC
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Tier 1
EGFR
Variants
EGFR K745_E746insIPVAIK
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Pleomorphic Carcinoma
Interpretation

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR exon 19 in-frame insertions have been described in about 1% of EGFR-mutant lung cancers. They appear to be more common in nonsmoking women. These exon 19 insertions appear to be sensitizing mutations and have been shown to respond to TKIs in some studies.

Last updated: 2016-05-18 23:02:30 UTC
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Tier 1
KIT
Variants
KIT exon(s) 9 insertion
Primary Sites
Stomach
Small Intestine
Rectum
Tumor Types
Gastrointestinal Stromal Tumor
Interpretation

KIT mutations occur in approximately 85% of patients with gastrointestinal stromal tumors (GIST), while Exon 9 is mutated in approximately 10 ~ 15% of all KIT-mutated GIST. Compared to patients with KIT exon 11 mutations, patients with exon 9 mutations tumors show intermediate sensitivity to imatinib. Median duration of benefit from imatinib is approximately 7~12 months compared to 23 months for patients with exon 11 mutations. Patients with exon 9 mutations are more likely to respond to second line sunitinib than patients with other KIT/PDGFRA mutations.

Last updated: 2017-02-22 15:23:03 UTC
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Tier 2
FGFR2
Variants
Primary Sites
Endometrium
Tumor Types
Adenocarcinoma
Interpretation

The receptor tyrosine kinase FGFR2 is one of four fibroblast growth factor receptors designated FGFR1-4 that activate FGF signalling upon trans-autophosphorylation of the receptor dimers. Some genetic alterations of FGFR2 lead to aberrant activation of FGFR2 signaling cascades due to the creation of autocrine signaling loop or the release of FGFR2 from autoinhibition. About 10-16% of primary endometrial cancers harbor activating mutations in FGFR2. These mutations are more frequent in cancers of endometrioid histological subtype compared with serous or clear-cell subtypes. Gain-of-function mutations in the kinase domain lead to ligand-independent activation of the receptor, whereas mutations in the extracellular ligand-binding domain increase the affinity for fibroblast growth factors (FGFs). Both types of mutations have been shown to be potentially oncogenic in endometrial cancer cell lines. In cell line and xenograft experiments, inhibition/knockdown of FGFR2 results in anti-tumour effects, suggesting the oncogenic role of FGFR2, raising the potential of FGFR2 as a target of therapy in FGFR2 driven cancers. Therefore, FGFR-pathway inhibition remains potentially promising in this patient population.

Last updated: 2016-06-01 13:38:33 UTC
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Tier 2
KRAS
Variants
Primary Sites
Endometrium
Tumor Types
Adenocarcinoma
Interpretation

KRAS belongs to the RAS family of oncogenes. KRAS mutations are detected in approximately 10-30% of endometrial tumors, predominantly within codons 12 or 13. KRAS mutations are also identified in endometrial hyperplasias, although at a lower frequency than in carcinomas. According to some studies, the gain of the KRAS function may represent an early event in endometrioid-type tumorigenesis. It has been shown that endometrioid carcinomas with significant mucinous component are more likely to have such mutations. KRAS gene amplification and protein overexpression but not mutation may be associated with aggressive and metastatic endometrial cancer according to some studies.

Last updated: 2016-06-01 13:43:34 UTC
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Tier 2
PTEN
Variants
Primary Sites
Endometrium
Tumor Types
Adenocarcinoma
Interpretation

PTEN is a tumor suppressor gene, located on chromosome 10q23. It encodes a lipid and protein phosphatase that negatively regulates the PI3K/AKT/mTOR pathway. Cancer-associated alterations in this gene often result in loss of PTEN protein and upregulation of the PI3K/AKT/mTOR pathway. Germline mutations of PTEN lead to inherited hamartoma and Cowden syndrome while somatic mutations are also known to occur in multiple malignancies, particularly as an early event in the development of endometrial cancer. PTEN gene sequence abnormalities are highly variable in type (frameshifts, point mutations) and can occur throughout all 9 exons. Germline mutations of PTEN, found in Cowden’s syndrome, are associated with an increased risk of endometrial cancer. Somatic mutations of PTEN occur in up to 50% of complex atypical hyperplasia and type I endometrial adenocarcinomas. Clinical trials assessing the efficacy of PI3K and mTOR inhibitors in PTEN loss are being explored.

Last updated: 2016-06-01 13:51:30 UTC
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Tier 3
SMAD4
Variants
Primary Sites
Breast
Tumor Types
Adenocarcinoma
Interpretation

SMAD4 is tumor suppressor gene and it encodes an intracellular mediator in the transforming growth factor β (TGF β) signal transduction pathway. Somatic mutations affecting the SMAD4 gene are rare in breast neoplasms and their role in breast tumorigenesis remains unclear. However, it has been demonstrated that SMAD4 protein expression is markedly downregulated or lost in breast ductal carcinoma when compared with that in the normal breast epithelium. Loss of SMAD4 protein expression may play a role in disease progression and overall prognosis in breast cancer patients but this need to be fully elucidated.

Last updated: 2016-06-01 13:53:34 UTC
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Tier 2
STK11
Variants
STK11 codon(s) 60-1 deletion
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Non-Small Cell Lung Carcinoma
Interpretation

The STK11 is a tumor suppressor gene located on chromosome 19p13.3. The encoded protein has serine-threonine kinase activity. Functionally, STK11 regulates cellular energy metabolism and cell polarity by activating AMP-activated protein kinase (AMPK) and other members of the AMPK family. Germline mutations in the STK11 gene are responsible for Peutz-Jeghers syndrome, an autosomal dominant disorder with variable clinical phenotype and increased risk of some cancers. Somatic mutations of STK11 gene are reported in several tumors including lung cancers. Studies have demonstrated STK11 inactivation is a common event and may be involved in the development of sporadic lung adenocarcinoma. Inactivation mutations of STK11 are found in 30% of lung cancer cell lines and in 15% of primary lung adenocarcinomas. Clinical relevance of these alterations and impact on disease progression and patient survival needs to be fully elucidated.

Last updated: 2020-07-24 14:52:46 UTC
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Tier 1
EGFR
Variants
EGFR E709_T710delinsD
EGFR exon(s) 18 indel
EGFR exon(s) 18 deletion
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Non-Small Cell Lung Carcinoma
Interpretation

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR exon 18 mutations account for 3.6% of all the EGFR mutations in lung adenocarcinomas. Of these, G719 mutations account for the majority of them and are sensitive to anti-EGFR inhibitors. Exon 18 deletions are rare (<0.1%) and but they are potentially responsive to anti-EGFR TKIs in some small clinical case studies. Of note, they appeared to be more sensitive to second-generation TKIs, especially afatinib and neratinib, than to first- and third-generation TKIs based on in vitro experiments.

Last updated: 2016-06-01 20:16:47 UTC
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Tier 2
ALK
Variants
ALK F1174L
ALK F1174C
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Non-Small Cell Lung Carcinoma
Interpretation

The anaplastic lymphoma kinase (ALK) has emerged as a potentially relevant biomarker and therapeutic target in a variety of solid and hematologic malignancies. It is a receptor tyrosine kinase (RTK) that is known to be activated either by point mutations or by chromosomal translocations. These genetic alterations act as oncogenic drivers and promote constitutive, ligand-independent activation of this RTK. Approximately 3-7% of non-small cell lung cancers (NSCLC) harbor ALK fusions/rearrangements. This fusion oncogene rearrangement is transforming both in vitro and in vivo and defines a distinct clinicopathologic subset of NSCLC that are highly sensitive to therapy with ALK-targeted inhibitors. While crizotinib is highly active in patients with ALK-positive NSCLC, patients have been shown to invariably develop resistance to this drug. In approximately one-third of resistant cases, tumors can acquire a secondary mutation within the ALK tyrosine kinase domain. ALK F1174 variant is a somatic mutation in the ALK kinase domain and has been detected in neuroblastomas. It has a transforming activity in vitro and in vivo, and may cause resistance to crizotinib as well as second generation ALK inhibitors such as ceritinib.

Last updated: 2020-07-24 14:52:34 UTC
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Tier 2
TSC1
Variants
TSC1 any missense
Primary Sites
Lung
Kidney
Bladder
Tumor Types
Adenocarcinoma
Urothelial Carcinoma
Renal Cell Carcinoma
Clear Cell Renal Cell Carcinoma
Interpretation

Germ line mutations of mutations in either TSC1 or TSC2 are found in 75-90% of cases of tuberous sclerosis complex (TSC), an autosomal dominant tumor syndrome associated with variable clinical phenotype including several hamrtomas and benign tumors. In addition, somatic alterations in these genes may occur in some tumor types. TSC1 and TSC2 both are tumor suppressor genes and their inactivation occurs by a classical two-hit mechanism. TSC1 is located on chromosome 9q34 and encodes hamartin. TSC2 is located on chromosome 16p13 and encodes tuberin. Hamartin and tuberin interact with and regulate a variety of proteins. These are negative regulators of the mTOR pathway, which is important for cell proliferation and frequently found activated in tumors. Mutation or deletion of TSC1 or TSC2 is found in 9-16 % of urothelial bladder tumors and up to 3% of clear cell renal cell carcinomas. More than 50% of bladder tumors of all grades and stages show LOH for markers on chromosome 9 and the TSC1 locus at 9q34 is a common critical region of deletion. Therefore, mTOR inhibitors have been identified as potential therapies for TSC1-mutated bladder cancers in some studies. LOH for the TSC1 or TSC2 locus has been described in 22% of 86 human lung cancer specimens. However, TSC1/2 sequence alterations are infrequent in lung and other epithelial malignancies.

Last updated: 2020-07-24 14:52:40 UTC
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Tier 1
EGFR
Variants
EGFR copy number gain
Primary Sites
Gastroesophageal Junction
Esophagus
Stomach
Tumor Types
Adenocarcinoma
Interpretation

Copy number gain (amplification) of EGFR has been reported in up to 30% of esophageal adenocarcinomas and less than 5% of gastric adenocarcinomas. According to some studies increased EGFR protein expression may be associated with decreased survival. This alteration may have therapeutic implications in some settings.

Last updated: 2016-06-01 21:09:54 UTC
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Tier 1
JAK2
Variants
JAK2 codon(s) 683 missense
JAK2 any mutation
Primary Sites
Bone Marrow
Blood
Tumor Types
B Lymphoblastic Leukemia/Lymphoma
Interpretation

Mutations at codon R683 of JAK2, have been previously described in B-ALL (especially Down Syndrome associated B-ALL) and represent a mutational "hotspot"; Some variants at this codon (R683) are known to be activating mutations. Cases of B-ALL with JAK2 mutations tend to also show rearrangement/overexpression of CRLF2; these are potentially targetable pathway alterations. Such cases tend to have a BCR/ABL-like transcriptional signature.

Last updated: 2018-11-12 20:41:32 UTC
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Tier 1
NOTCH1
Variants
NOTCH1 exon(s) 34 frameshift
NOTCH1 exon(s) 34 nonsense
NOTCH1 exon(s) 34 missense
Primary Sites
Blood
Bone Marrow
Tumor Types
Chronic Lymphocytic Leukemia
Interpretation

NOTCH1 mutations have also recently been reported in approximately 10% of chronic lymphocytic leukemia and are typically PEST domain mutations in that disease. In CLL, NOTCH1 mutations and tend to be exlusive of SF3B1 mutations and possibly TP53 mutations, although some studies demonstrate that NOTCH1 mutations are associated with mutations of TP53. In CLL, the presence of NOTCH1 mutations has been associated with trisomy 12 and aggressive biologic features(CD38+, ZAP70+, unmutated IgH variable region) and adverse prognosis in some settings. The potential utility of therapeutic targeting of activating NOTCH1 mutations in these diseases remains to be elucidated.

Last updated: 2016-06-04 23:28:05 UTC
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Tier 1
TP53
Variants
TP53 copy number loss
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Interpretation

TP53 is a well known tumor suppressor gene that is mutated in wide variety of cancers. In terms of myeloid disorders, missense, nonsense, and frameshift mutations of TP53 tend to occur in the DNA binding domain and have been reported in approximately 4% of cases of AML where they tend to be associated with a poorer prognosis and an adverse cytogenetic risk profile. TP53 mutations also occur in approximately 10% of patients with myelodysplastic syndrome (MDS) and are often associated with poorer prognosis, adverse cytogenetic profile and deletion of 5q either in isolation or as part of a complex karyotype.

Last updated: 2016-06-05 01:55:37 UTC
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Tier 1
TP53
Variants
TP53 copy number loss
Primary Sites
Blood
Bone Marrow
Tumor Types
B Lymphoblastic Leukemia/Lymphoma
Interpretation

TP53 is a well known tumor suppressor gene that is mutated in wide variety of cancers. Among cases of acute lymphoblastic leukemia, overall TP53 mutations are reported to occur in less than 10% of cases. However, TP53 mutations have a very high prevalence (approximately 90%) among cases of ALL with low hypodiploid karyotype and in this setting are often associated with monosomy 17 and may be associated with germline TP53 mutations in a significant proportion of such cases in children.

Last updated: 2016-06-05 01:58:34 UTC
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Tier 2
TSC2
Variants
TSC2 any missense
Primary Sites
Lung
Kidney
Bladder
Tumor Types
Adenocarcinoma
Clear Cell Renal Cell Carcinoma
Renal Cell Carcinoma
Urothelial Carcinoma
Interpretation

Germ line mutations of mutations in either TSC1 or TSC2 are found in 75-90% of cases of tuberous sclerosis complex (TSC), an autosomal dominant tumor syndrome associated with variable clinical phenotype including several hamrtomas and benign tumors. In addition, somatic alterations in these genes may occur in some tumor types. TSC1 and TSC2 both are tumor suppressor genes and their inactivation occurs by a classical two-hit mechanism. TSC1 is located on chromosome 9q34 and encodes hamartin. TSC2 is located on chromosome 16p13 and encodes tuberin. Hamartin and tuberin interact with and regulate a variety of proteins. These are negative regulators of the mTOR pathway, which is important for cell proliferation and frequently found activated in tumors. Mutation or deletion of TSC1 or TSC2 is found in 9-16 % of urothelial bladder tumors and up to 3% of clear cell renal cell carcinomas. More than 50% of bladder tumors of all grades and stages show LOH for markers on chromosome 9 and the TSC1 locus at 9q34 is a common critical region of deletion. Therefore, mTOR inhibitors have been identified as potential therapies for TSC1-mutated bladder cancers in some studies. LOH for the TSC1 or TSC2 locus has been described in 22% of 86 human lung cancer specimens. However, TSC1/2 sequence alterations are infrequent in lung and other epithelial malignancies.

Last updated: 2020-07-24 14:52:56 UTC
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Tier 3
MLH1
Variants
MLH1 V384D
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Interpretation

MLH1 is a component of the cellular DNA mismatch repair (MMR) machinery causing hereditary nonpolyposis colorectal cancer (HNPCC), and is associated with specific somatic alterations in the tumor, characterized by high microsatellite instability (MSI-H). The MLH1 V384D mutation has been associated with cancer risk in some tumor types. This variant encodes in a partially impaired protein with diminished interaction with PMS2 protein and reduced MMR activity in vitro. The MLH1 V384D variant has not been reported in thyroid tumors. However, some other MLH1 variants have been described in some thyroid tumors, but their clinical significance is yet to be determined. Of note, according to one report, MLH1 V384D variant has been reported to be associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma. Clinical correlation is recommended.

Last updated: 2017-01-30 21:13:28 UTC
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Tier 2
CDH1
Variants
Primary Sites
Stomach
Tumor Types
Adenocarcinoma
Interpretation

CDH1 on 16q22.1 encodes E-cadherin which functions in intercellular adhesion. E-cadherin is involved in transmitting chemical signals and controlling cell maturation and movement, and acts as a tumor suppressor. A lack of functional E-cadherin impairs cell adhesion and increases the likelihood of invasion and metastasis of tumor cells. More than 100 different pathogenic germline mutations are distributed throughout the CDH1 gene including splice-site sequences and have been found to cause a familial cancer disorder called hereditary diffuse gastric cancer (HDGC). Somatic CDH1 alterations are also found in approximately 30% of all patients with gastric cancers, both diffuse and intestinal types. CDH1 mutation identification in HDGC families is clinically important to assess the risk of gastric and breast cancers in unaffected relatives. Prognostic and therapeutic implications of this alterations remain to be fully elucidated. The 50 gene panel hotspot assay can not distinguish between germline or somatic(acquired) variants. Correlation with other clinical and lab findings, including genetic counseling, may be helpful, if clinically indicated.

Last updated: 2016-06-25 19:43:17 UTC
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Tier 2
IDH2
Variants
IDH2 R140Q
IDH2 codon(s) 140, 172 any
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Squamous Cell Carcinoma
Non-Small Cell Lung Carcinoma
Interpretation

IDH2 is a mitochondrial enzyme involved in citrate metabolism. Mutations at Arg140 and Arg172 of IDH2 are typically heterozygous and are considered gain-of-function mutations that lead to increased levels of 2-hydroxyglutarate believed to alter epigenetic regulation in various tumors, especially in myeloid neoplasms. The Arg140 mutation of IDH2 has not been reported previously in lung tumors. However, a few other IDH2 mutations have been described in non-small cell lung cancers (NSCLC) in a very small number of patients in the literature. The prognostic impact of IDH2 mutations in NSCLC remains uncertain at this time. Mutant IDH2 may provide a potential therapeutic target in some settings. Clinical correlation is recommended.

Last updated: 2016-06-25 19:44:17 UTC
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Tier 1
BRAF
Variants
BRAF L597V
BRAF L597R
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. BRAF mutations are present in approximately 50% to 60% of cutaneous melanomas and are also present at lower frequencies in other melanoma subtypes. A point mutation, L597R, is located in the kinase domain of BRAF. A case report has shown that a metastatic melanoma with this mutation is sensitive to BRAF inhibitors. In addition, it has been suggested that BRAF L597 mutations could potentially be responsive to MEK inhibitors. Drug: Trametinib BGB659

Last updated: 2018-04-06 15:07:07 UTC
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Tier 3
PTPN11
Variants
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Squamous Cell Carcinoma
Non-Small Cell Lung Carcinoma
Interpretation

The PTPN11gene encodes SHP-2, a widely expressed cytoplasmic protein tyrosine phosphatase. SHP-2 is essential for activation of the RAS/MAPK signaling cascade. Most mutations are gain-of-function and result in prolonged ligand-dependent activation of the RAS/MAPK cascade. Germ-line PTPN11 mutations cause Noonan syndrome, a developmental disorder characterized by an increased risk of malignancies. Activating somatic mutations in PTPN11 have been documented in certain hematologic malignancies but they are infrequent in solid tumors. About 3% of all lung cancers harbor somatic mutations in PTPN11 gene but their prognostic and therapeutic significance remains to be fully elucidated. The utility of SHP2 inhibitors continues to be explored in some preclinical studies.

Last updated: 2016-06-25 19:48:14 UTC
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Tier 2
KRAS
Variants
Primary Sites
Prostate
Tumor Types
Adenocarcinoma
Interpretation

KRAS belongs to the RAS family of oncogenes. KRAS mutations in codons 12 and 13 were found in 6-7% of prostatic adenocarcinomas. KRAS gene rearrangement has been reported in 3% of metastatic prostate cancer. Prognostic and predictive implications of KRAS gene alterations in prostate cancer need to be fully elucidated.

Last updated: 2016-08-01 19:23:22 UTC
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Tier 3
SMAD4
Variants
SMAD4 R361H
Primary Sites
Stomach
Tumor Types
Adenocarcinoma
Carcinoma
Interpretation

SMAD4 is a tumor suppressor gene and it encodes an intracellular mediator in the transforming growth factor β (TGF β) signal transduction pathway. The gene is inactivated in 40% of human gastric cancers by loss of heterozygosity, promoter hypermethylation, and somatic mutation. Prior sequencing studies have shown that SMAD4 is mutated in up to 8% of gastric cancers. SMAD4 p.R361H mutation occurs within the MH2 domain which is the SMAD-SMAD interaction and transcription activation domain of the protein. The loss of SMAD4, especially loss of nuclear SMAD4 expression, is involved in gastric cancer progression. Mutations at codon 361 have been previously reported in various tumor types. The exact clinical significance of this mutation in gastric cancers needs to be fully elucidated.

Last updated: 2016-10-11 21:49:56 UTC
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Tier 2
KRAS
Variants
Primary Sites
Esophagus
Gastroesophageal Junction
Tumor Types
Adenocarcinoma
Carcinoma
Interpretation

KRAS is a gene that encodes one of the several proteins in the epidermal growth factor receptor (EGFR) signaling pathway that is important in the development and progression of cancer. KRAS can harbor oncogenic mutations that yield a constitutively active protein. KRAS mutations are found in approximately 2-3% of esophageal cancers. In colorectal cancers, mutations in the KRAS gene may indicate poor prognosis and poor drug responses against anti-EGFR therapies. However, prognostic and predictive implications of KRAS mutations in esophageal cancers need to be fully elucidated. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2016-10-11 21:50:35 UTC
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Tier 2
EGFR
Variants
EGFR T790M
Primary Sites
Stomach
Tumor Types
Adenocarcinoma
Squamous Cell Carcinoma
Interpretation

EGFR mutations have been reported in up to 5% of gastric cancers. The prognostic and predictive implications of EGFR mutations in gastric cancer have not been fully determined. Multiple clinical trials involving EGFR small molecule inhibitors and monoclonal antibodies are present, but limited and conflicting data preclude the therapeutic significance of EGFR mutations in gastric cancer. In NSCLC, an acquired T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. Third generation TKIs (e.g. osimertinib) have been shown to be effective in lung adenocarcinomas with the EGFR T790M mutation. A germline EGFR T790M mutation results in a rare lung cancer hereditary syndrome associated with increased risk in never-smokers. The presence of a germline EGFR T790M mutation also predicts for resistance to standard TKIs. The significance of EGFR T790M in gastric cancer should be considered in a relevant clinical context. Drug Resistance: Afatinib Erlotinib Gefitinib

Last updated: 2018-04-18 14:23:32 UTC
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Tier 3
CTNNB1
Variants
Primary Sites
Lung
Tumor Types
Non-Small Cell Lung Carcinoma
Interpretation

The cytoplasmic β-catenin protein is implicated as a cell-cell adhesion regulator coupled with cadherin and is considered as a member in the wingless/Wnt signal transduction pathway. Mutations in CTNNB1, the gene encoding β-catenin, tend to impact or even eliminate APC-dependent serine and threonine phosphorylation sites in exon 3, resulting in oncogenic stabilization of the protein. Increased protein within the nuclei serves as a transcriptional factor through binding to the Tcf/Lef family. Mutations in the β-catenin gene are uncommon in NSCLC occurring in about 1-4% of the cases. Nuclear accumulation of β-catenin was found to be associated with EGFR mutations, and β-catenin overexpression was associated with NSCLC cell line resistance to gefitinib. Wnt pathway inhibitors are in preclinical development or have entered early clinical trials. Because high β-catenin expression has been associated with good outcome rather than with poor outcome in NSCLC patients, it could potentially prove important to target specific downstream β-catenin functions rather than using agents that could directly suppress β-catenin levels through upstream targeting of the Wnt pathway.

Last updated: 2016-08-01 19:47:33 UTC
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Tier 2
BRAF
Variants
BRAF G466V
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Non-Small Cell Lung Carcinoma
Carcinoma
Melanoma
Interpretation

Somatic mutations in BRAF have been found in 1--4% of all NSCLC most of which are adenocarcinomas. The G466V mutation results in an amino acid substitution within the kinase domain of BRAF. Unlike other mutant BRAF proteins, G466V shows decreased kinase activity. In preclinical studies, lung cancer cell lines with G466V mutation were sensitive to TKI dasatinib, presumably by induction of tumor cell senescence. However, therapeutic implications of BRAF inhibitors in patients with this mutation need to be fully elucidated. Drug: Trametinib

Last updated: 2018-11-12 20:40:30 UTC
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Tier 1
EGFR
Variants
EGFR L747P
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Non-Small Cell Lung Carcinoma
Interpretation

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR L747P (c.2239_2240 TT>CC) is a rare missense compound substitution mutation in the Exon 19 and has been reported to be resistant to some EGFR inhibitors.

Last updated: 2016-08-01 20:01:33 UTC
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Tier 2
PTEN
Variants
PTEN any frameshift
PTEN any deletion
PTEN any missense
Primary Sites
Breast
Tumor Types
Invasive Ductal Carcinoma
Adenocarcinoma
Interpretation

PTEN is an obligate haplo-insufficient tumor suppressor gene and is commonly mutated in a large number of cancers. It negatively regulates intracellular levels of Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in cells and functions as a tumor suppressor by negatively regulating AKT/mTOR signaling pathway. Mono- and bi-allelic loss of PTEN is found in approximately 40-50% and 5% of breast cancers, respectively. It has been reported to occur in BRCA1-associated basal-like breast cancer. Germline mutations in PTEN are also responsible for Cowden disease, a rare autosomal dominant multiple-hamartoma syndrome. In one study, germline mutations of PTEN have been reported to be associated with 85% lifetime risk of breast cancer in patients with PTEN hamartoma tumor syndrome. Aberrant PTEN pathway is associated with metastases and poor prognosis in breast cancer. It also predicts poor response to trastuzumab. There are ongoing clinical trials investigating anti-tumor activity of PI3K-beta inhibitor in PTEN deficient tumors.

Last updated: 2016-08-12 16:31:08 UTC
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Tier 2
EGFR
Variants
Primary Sites
Stomach
Tumor Types
Adenocarcinoma
Interpretation

EGFR mutations have been reported in up to 5% of gastric cancers. The prognostic and predictive implications of EGFR mutations in gastric cancer have not been fully determined. Multiple clinical trials involving EGFR small molecule inhibitors and monoclonal antibodies are present, but limited and conflicting data preclude the therapeutic significance of EGFR mutations in gastric cancer.

Last updated: 2016-10-11 21:48:32 UTC
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Tier 3
PTEN
Variants
PTEN any frameshift
PTEN any deletion
PTEN any missense
Primary Sites
Stomach
Tumor Types
Adenocarcinoma
Interpretation

PTEN is an obligate haplo-insufficient tumor suppressor gene and is commonly mutated in a large number of cancers. It negatively regulates intracellular levels of Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in cells and functions as a tumor suppressor by negatively regulating AKT/mTOR signaling pathway. PTEN mutations have been reported in up to 19% of gastric cancers. Germline mutations in PTEN are also responsible for Cowden disease, a rare autosomal dominant multiple-hamartoma syndrome. Patients with Cowden disease can have gastric polyps, but a possible association with gastric cancer needs further study. Inactivation of PTEN is shown to be closely associated with tumor progression and metastases. Clinical trials using PI3K-beta inhibitor are available for patients with PTEN-deficient tumors.

Last updated: 2016-10-11 21:49:10 UTC
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Tier 2
ERBB2
Variants
ERBB2 L755S
Primary Sites
Breast
Tumor Types
Adenocarcinoma
Invasive Ductal Carcinoma
Interpretation

ERBB2 kinase domain mutations are seen in up to 4.3% of breast cancers. In vitro analyses demonstrated that L755S confer resistance to lapatinib and could potentially emerge as an acquired mutation during therapy. Another preclinical study has shown that L755S is sensitive to irreversible TKIs neratinib and canertinib. The predictive and prognostic as well as therapeutic implications of ERBB2 mutations need further elucidation.

Last updated: 2016-08-12 16:39:15 UTC
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Tier 3
CDKN2A
Variants
CDKN2A copy number loss
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Follicular Carcinoma
Interpretation

CDKN2A gene encodes p16 and functions as an important tumor suppressor in various human malignancies. Its activation prevents carcinogenesis via induction of cell growth arrest and senescence. Majority of the CDKN2A mutations span exon 2 and result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. Genetic alterations (deletion, mutation, and methylation) in p16 associated with loss of function have been reported in cell lines and primary thyroid tumors. However, predictive or prognostic significance of p16 in thyroid cancer is not clear and correlation with other clinical and lab findings is necessary. Multiple clinical trials are available for patients with CDKN2A deficient tumors.

Last updated: 2016-08-12 21:53:06 UTC
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Tier 2
CDKN2A
Variants
CDKN2A copy number loss
Primary Sites
Stomach
Tumor Types
Adenocarcinoma
Interpretation

CDKN2A generates several transcript variants including p16 and p14ARF. P16 regulates cell cycle by inhibiting CDK4 and CDK6, and thus preventing progression from G1 to S phase. P14ARF acts as a tumor suppressor by inhibiting ribosome biogenesis and initiating p53-dependent cell cycle arrest and apoptosis. Mutations and deletion of CDKN2A are reported in up to 34% of gastric cancer. In addition, EBV-positive gastric adenocarcinoma showed CDKN2A promoter hypermethylation. Gastric cancer with CDKN2A mutations has been shown to be sensitive to CDK4/6 inhibitors in vitro studies. However, predictive or prognostic significance of CDKN2A mutation in gastric cancer is not clear and correlation with other clinical and laboratory findings is necessary. Multiple clinical trials are available for patients with CDKN2A deficient tumors.

Last updated: 2020-07-24 14:53:03 UTC
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Tier 1
KIT
Variants
KIT V559A
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

KIT mutations are seen in up to 17% of cutaneous melanomas. The V559A mutation in exon 11 occurs within the juxtamembrane domain. In vitro studies have shown that mutant KIT proteins have increased kinase activity. KIT activating mutations in exons 11 and 13 are typically sensitive to treatment with Imatinib. There are multiple clinical trials available for patients with melanomas harboring KIT alterations.

Last updated: 2016-08-31 22:08:06 UTC
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Tier 2
EGFR
Variants
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Follicular Carcinoma
Interpretation

EGFR mutations have been reported in 1-3% of thyroid cancers. The prognostic and predictive significance of EGFR mutations in thyroid cancer is not clear and correlation with other clinical and laboratory findings is necessary. Clinical trials involving protein kinase inhibitor are available for patients with tumors harboring EGFR mutations.

Last updated: 2016-08-31 22:11:48 UTC
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Tier 2
PIK3CA
Variants
PIK3CA E542K
PIK3CA E545K
PIK3CA H1047R
PIK3CA codon(s) 542, 545, 1047 any
Primary Sites
Anus
Oral Cavity
Pharynx
Lung
Tumor Types
Squamous Cell Carcinoma
Interpretation

The catalytic subunit (p110a) of phosphatidylinositol-3-kinase (PI3K) is encoded by the PIK3CA gene and acts to activate several signaling cascades, including the well-characterized AKT-mTOR pathway that promotes cell survival, proliferation, growth and motility. PIK3CA is among the most commonly mutated genes in cancer and aberrant activation of PI3K is a transforming event. Somatic mutations in PIK3CA have been found in 1--3% of NSCLC and genetic alteration in PIK3CA have been identified in 7% of lung adenocarcinomas. These mutations typically occur within specific hotspot regions. PIK3CA mutations activate the PI3K-PTEN-AKT pathway which is downstream from both the EGFR and the RAS-RAF-MAPK pathways. The somatic mutations found thus far in PIK3CA are oncogenic, and the majority of them are clustered within exon 9 and 20 (helical and kinase domains), with three hotspots (E542K, E545K, and H1047R/L). PIK3CA mutations have been reported in 8-21% and 20-33% of head/neck and anal squamous cell carcinoma, respectively. PIK3CA mutations, especially ones involving the helical domain, in these types of squamous cell carcinoma are highly associated with HPV. The predictive and prognostic significance of PIK3CA mutations in squamous cell carcinoma is unclear and needs further elucidation. Clinical trials targeting PI3K/Akt/mTor pathway inhibitors are available for patients with PIK3CA mutated tumors.

Last updated: 2019-03-11 16:30:45 UTC
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Tier 2
HRAS
Variants
HRAS codon(s) 12, 13, 61 any
HRAS Q61R
HRAS Q61K
Primary Sites
Anus
Vulva
Oral Cavity
Pharynx
Larynx
Tumor Types
Squamous Cell Carcinoma
Interpretation

RAS is a family of small GTPases and acts as an oncogene. Point mutations in codons 12 and 13 of RAS gene increases its affinity for GTP and those in codon 61 inactivate its autocatalytic GTPase function, resulting in permanent RAS activation and stimulation of its downstream targets along the MAPK and PI3K/AKT signaling pathways. HRAS mutation has been reported in up to 5% and 9% of head/neck and vulvar squamous cell carcinoma, respectively. The predictive and prognostic significance of HRAS mutations in squamous cell carcinoma is unclear and needs further elucidation.

Last updated: 2018-12-14 14:07:45 UTC
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Tier 2
KRAS
Variants
KRAS V14I
Primary Sites
Colon
Tumor Types
Adenocarcinoma
Interpretation

KRAS belongs to a family of small GTPases and gain-of-function mutations in the gene yield a constitutively active protein. Such mutations are found in approximately 30% to 50% of metastatic colorectal cancers and are common in other tumor types. The most frequent KRAS mutations occur at codons 12, 13, and 61. Mutations at codons 117 and 146 are less common. Mutations at codon 14 have been detected in adenocarcinomas of the small intestine and colon as well as AML. Germline V14I mutations have been identified in patients with Noonan syndrome. In vitro studies have shown that V14I mutations lead to moderately enhanced MEK1/2 and ERK1/2 phosphorylation suggesting increased downstream signaling, but with slightly less transforming capacity than G12D mutation. Mutations in the KRAS gene may indicate poor prognosis and poor drug response to EGFR-targeted therapies. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2016-10-11 21:38:34 UTC
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Tier 2
ALK
Variants
ALK L1196M
ALK L1196Q
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Non-Small Cell Lung Carcinoma
Interpretation

The anaplastic lymphoma kinase (ALK) has emerged as a potentially relevant biomarker and therapeutic target in a variety of solid and hematologic malignancies. It is a receptor tyrosine kinase (RTK) that is known to be activated either by point mutations or by chromosomal translocations. These genetic alterations act as oncogenic drivers, promoting constitutive, ligand-independent activation of this RTK. Approximately 3-7% of non-small cell lung cancers (NSCLC) harbor ALK fusions/rearrangements. ALK fusion oncogenes are transforming both in vitro and in vivo, defining a distinct clinicopathologic subset of NSCLC that are highly sensitive to therapy with ALK-targeted inhibitors. While crizotinib (ALK/MET TKI) is highly active in patients with ALK-positive NSCLC, patients have been shown to invariably develop resistance to this drug. In approximately one-third of resistant cases, tumors can acquire a secondary mutation within the ALK tyrosine kinase domain. L1196 is present in the gatekeeper position at the bottom of the ATP-binding pocket of the protein. Gatekeeper genetic alterations seem to confer TKI resistance in oncogenic tyrosine kinases. L1196M mutant confers high-level resistance to crizotinib, but has been shown to be sensitive to ceretinib.

Last updated: 2020-07-24 14:53:09 UTC
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Tier 2
ALK
Variants
ALK G1202R
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Non-Small Cell Lung Carcinoma
Interpretation

The anaplastic lymphoma kinase (ALK) has emerged as a potentially relevant biomarker and therapeutic target in a variety of solid and hematologic malignancies. It is a receptor tyrosine kinase (RTK) that is known to be activated either by point mutations or by chromosomal translocations. These genetic alterations act as oncogenic drivers, promoting constitutive, ligand-independent activation of this RTK. Approximately 3-7% of non-small cell lung cancers (NSCLC) harbor ALK fusions/rearrangements. ALK fusion oncogenes are transforming both in vitro and in vivo, defining a distinct clinicopathologic subset of NSCLC that are highly sensitive to therapy with ALK-targeted inhibitors. While crizotinib (ALK/MET TKI) is highly active in patients with ALK-positive NSCLC, patients have been shown to invariably develop resistance to this drug. In approximately one-third of resistant cases, tumors can acquire a secondary mutation within the ALK tyrosine kinase domain. ALK G1202R is postulated to be in the solvent-exposed region abutting the crizotinib-binding site, likely diminishing the binding affinity of crizotinib and other ALK inhibitors to the mutant ALK. G1202R has been shown to cause resistance to crizotinib as well as second generation ALK inhibitors (ceritinib, alectinib).

Last updated: 2020-07-24 14:53:15 UTC
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Tier 2
PIK3CA
Variants
PIK3CA E542K
PIK3CA E545K
PIK3CA H1047R
PIK3CA codon(s) 542, 545, 1047 any
Primary Sites
Liver
Pancreas
Stomach
Tumor Types
Hepatocellular Carcinoma
Adenocarcinoma
Cholangiocarcinoma
Interpretation

PIK3CA mutations activate the PI3K-PTEN-AKT pathway which is downstream from both the EGFR and the RAS-RAF-MAPK pathways. The somatic mutations found thus far in PIK3CA are oncogenic, and the majority of them are clustered within exon 9 and 20 (helical and kinase domains), with three hotspots (E542K, E545K, and H1047R/L). PIK3CA mutations have been reported in various tumor types including up to 36% and 11% of hepatocellular carcinoma and gastric cancer, respectively. They are detected less frequently in cholangiocarcinoma (~6%) and pancreatic adenocarcinoma (~4%). The predictive and prognostic significance of PIK3CA mutations is unclear and needs further elucidation. Clinical trials targeting PI3K/Akt/mTor pathway inhibitors are available for patients with PIK3CA mutated tumors.

Last updated: 2016-10-05 22:29:42 UTC
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Tier 2
BRAF
Variants
BRAF G469A
Primary Sites
Colon
Tumor Types
Adenocarcinoma
Interpretation

BRAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. Approximately 8-15% of colorectal cancer (CRC) harbors BRAF mutations. BRAF G469A mutation in exon 11 is infrequent in CRC and occurs within the kinase domain. The presence of BRAF mutation is significantly associated with right-sided colon cancers and is associated with decreased overall survival. BRAF mutation in a microsatellite unstable colorectal carcinoma indicates that the tumor is probably sporadic and not associated with Lynch syndrome (HNPCC). However, if a BRAF mutation is not detected, the tumor may either be sporadic or Lynch syndrome associated. Detection of BRAF mutations may also be useful in determining patient eligibility for anti-EGFR treatment. Some studies have reported that patients with metastatic CRC (mCRC) that harbor BRAF mutations do not respond to anti-EGFR antibody agents (cetuximab or panitumumab) in the chemotherapy-refractory setting. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2020-07-24 14:53:21 UTC
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Tier 3
PIK3CA
Variants
Primary Sites
Prostate
Tumor Types
Adenocarcinoma
Carcinoma
Interpretation

PIK3CA mutations activate the PI3K-PTEN-AKT pathway which is downstream from both the EGFR and RAS-RAF-MAPK pathways. The somatic mutations found thus far in PIK3CA are oncogenic, and the majority of them are clustered within exon 9 and 20 (helical and kinase domains). Activating mutations in PIK3CA are found in a wide variety of human cancers including up to 4% of prostate cancers. The role of PIK3CA mutations as prognosticators of outcome or predictors of therapeutic response awaits further evaluation. Clinical trials are available for patients with PIK3CA mutated tumors.

Last updated: 2016-10-23 21:58:06 UTC
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Tier 3
MET
Variants
MET E168D
Primary Sites
Prostate
Tumor Types
Adenocarcinoma
Carcinoma
Interpretation

MET is a member of the receptor tyrosine kinase and proto-oncogene playing a major role in tumor development and metastasis. MET mutations have been reported in 1% of primary prostate cancers and up to 4.4% of metastatic prostate cancers. Studies have suggested that overexpression of c-MET and aberrant activation of the HGF/c-MET axis in prostate cancer is a relatively late event in tumor progression seen in advanced stages of the disease. MET E168D mutation is located in the SEMA domain containing the ligand binding site. The prognostic and predictive significance of MET mutations in prostate cancer is not clear and correlation with other clinical and laboratory findings is necessary.

Last updated: 2016-10-23 22:02:16 UTC
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Tier 2
KRAS
Variants
Primary Sites
Kidney
Ureter
Tumor Types
Urothelial Carcinoma
Interpretation

KRAS belongs to the RAS family of oncogenes and is important in the development and progression of a variety of cancers. KRAS can harbor oncogenic mutations that yield a constitutively active protein. The frequency of KRAS gene mutations in upper tract urothelial carcinoma is low (5%). In the context of urothelial carcinoma of the bladder, mutations in the KRAS gene do not appear to be predictors for recurrence-free, progression-free and disease-specific survival according to some studies. The prognostic and predictive role of KRAS mutations in upper tract urothelial carcinoma needs to be further elucidated.

Last updated: 2016-11-04 00:36:09 UTC
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Tier 2
PTEN
Variants
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

PTEN is an obligate haplo-insufficient tumor suppressor gene and is commonly mutated in a large number of cancers. It negatively regulates intracellular levels of Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in cells and functions as a tumor suppressor by negatively regulating AKT/mTOR signaling pathway. PTEN somatic point mutations are infrequent, but allelic loss or altered expression is seen in approximately 20% and 40% of the melanoma cases, respectively. Clinical trials using PI3K-beta inhibitor are available for patients with PTEN-deficient tumors.

Last updated: 2016-11-04 00:38:40 UTC
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Tier 2
CDKN2A
Variants
CDKN2A copy number loss
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

CDKN2A gene functions as an important tumor suppressor via induction of cell growth arrest and senescence. Majority of the CDKN2A mutations result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. CDKN2A is the major high-risk susceptibility gene identified in melanoma. Somatic mutations of CDKN2A are reported in up to 19% and 20% of cutaneous and desmoplastic melanoma, respectively. Germline mutations have been reported in ~20-40% of families with melanoma. Correlation with other clinical and lab findings is necessary.

Last updated: 2016-11-04 00:44:59 UTC
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Tier 2
CDKN2A
Variants
CDKN2A copy number loss
Primary Sites
Liver
Tumor Types
Hepatocellular Carcinoma
Interpretation

CDKN2A gene functions as an important tumor suppressor via induction of cell growth arrest and senescence. Majority of the CDKN2A mutations result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. Somatic mutations of CDKN2A are present in various tumor types including ~2-3% of hepatocellular carcinoma (HCC). However, epigenetic silencing of CDKN2A by promoter hypermethylation is more frequent, occurring in 73% of HCC, 56% of HBV-related HCC, and 84% of HCV-related HCC. Clinical trials for CDKN2A deficient tumors are available. Correlation with other clinical and lab findings is necessary.

Last updated: 2016-11-04 00:46:32 UTC
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Tier 1
BRAF
Variants
BRAF N581S
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. BRAF mutations are present in approximately 50% to 60% of cutaneous melanomas and are also present at lower frequencies in other melanoma subtypes. A point mutation, N581S, is located in the kinase domain of BRAF. It has been reported that N581S is associated with intermediate kinase activity. Correlation with other clinical and lab findings is necessary.

Last updated: 2017-02-04 21:12:09 UTC
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Tier 3
MET
Variants
MET E168D
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

MET is a member of the receptor tyrosine kinase and proto-oncogene playing a major role in tumor development and metastasis. Mutations in MET have been reported in 4-9% of cutaneous melanoma. MET E168D has not been reported in melanomas. This mutation is located in a conserved domain containing the ligand binding site. In vitro studies have shown that E168D may be associated with higher ligand affinity and higher susceptibility to c-Met inhibitors in lung cancer. The prognostic and predictive significance of MET mutations in melanoma is not clear and correlation with other clinical and laboratory findings is necessary.

Last updated: 2016-11-04 01:04:05 UTC
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Tier 2
RB1
Variants
Primary Sites
Brain
Tumor Types
Glioblastoma
Interpretation

The protein encoded by the RB1 gene is a negative regulator of the cell cycle and was the first tumor suppressor gene identified. The active, hypophosphorylated form of the protein binds transcription factor E2F1. RB1 alterations including mutations and deletions are seen in up to 11% of glioblastomas. It has been suggested that patients with RB1-deficient tumors do not respond to cyclin-dependent kinase (CDK) inhibitors. The predictive and prognostic significance of RB1 mutations in glioblastoma needs to be further studied.

Last updated: 2017-01-03 16:42:29 UTC
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Tier 2
KIT
Variants
Primary Sites
Thymus
Tumor Types
Thymic Carcinoma
Interpretation

KIT is a growth factor receptor of the tyrosine kinase subclass III family, normally expressed in a variety of human tissues. Somatic mutations of KIT are only identified in ~ 4% of thymic carcinoma, but KIT protein overexpression has been observed in up to 88% of cases. Valine at amino acid position 560 (V560) is located in exon 11 within the juxtamembrane domain of KIT, and an in-frame deletion of V560 results in an activating mutation. A case report has described a patient with thymic carcinoma harboring KIT V560del who had a partial response to imatinib. In another case, patient who has kit mutation in his thymic carcinoma achieved 27 moths of disease control with imatinib followed by sunitinib. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2017-03-14 02:16:03 UTC
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Tier 2
CDH1
Variants
CDH1 any indel
Primary Sites
Breast
Tumor Types
Interpretation

CDH1 on 16q22.1 encodes E-cadherin which functions in intercellular adhesion. E-cadherin is involved in transmitting chemical signals and controlling cell maturation and movement, and acts as a tumor suppressor. A lack of functional E-cadherin impairs cell adhesion and increases the likelihood of invasion and metastasis of tumor cells. Invasive lobular breast cancer (ILC) accounts for 10-15% of invasive breast cancers and is characterized by loss of E-cadherin expression due to mutations, loss of heterozygosity and hypermethylation. Germline CDH1 mutations have been found to cause a familial cancer disorder called hereditary diffuse gastric cancer (HDGC). CDH1 mutation identification in HDGC families has important clinical implications for gastric and breast cancers risk assessment in unaffected family members. The estimated risk for invasive lobular carcinoma in females with germline CDH1 mutations is approximately 40% by age 80 years. Prognostic and therapeutic implications of this alteration remain to be fully elucidated. The 50 gene panel hotspot assay cannot distinguish between germline or somatic (acquired) variants. Correlation with other clinical and lab findings, including genetic counseling, may be helpful, if clinically indicated.

Last updated: 2017-01-03 17:50:11 UTC
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Tier 1
GNA11
Variants
Primary Sites
Eye
Tumor Types
Melanoma
Interpretation

This gene is often mutated in uveal melanoma (Van Raamsdonk, et al. 2010). A frequent mutation in GNA11 (Q209) can promote disease progression. Combined mTOR/PI3K and MEK inhibition is showing promises in preclinical studies (Khalili et al, 2012). In addition, a randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy showed selumetinib resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events (Carvajal et al, 2014). Also, GNAQ and GNA11 mutations occur in 9.5% of mucosal melanoma and are associated with poor prognosis (Sheng et al, 2016).

Last updated: 2017-01-08 19:17:13 UTC
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Tier 1
SMO
Variants
Primary Sites
Skin
Tumor Types
Basal Cell Carcinoma
Interpretation

Basal cell carcinoma (BCC) is primarily driven by the Sonic Hedgehog (Hh) pathway. Eighty-five percent of the BCCs harbors mutations in Hh pathway genes. In basal cell carcinoma, activating mutations in SMO are associated with sensitivity to Hedgehog pathway inhibitors.

Last updated: 2017-01-08 23:07:33 UTC
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Tier 1
PIK3CA
Variants
PIK3CA E545K
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations in PIK3CA have been found in 10-30% of colorectal cancers. KRAS, NRAS, BRAF and PIK3CA and non-functional PTEN predict resistance to anti-EGFR therapies in metastatic colorectal cancer. According to some reports, co-occurrence of both exon 9 and exon 20 PIK3CA mutations, when present, may be associated with a poor prognosis. Recent 'molecular pathological epidemiology' (MPE) research has shown that aspirin use may be associated with better prognosis and clinical outcome in PIK3CA-mutated colorectal carcinoma, suggesting somatic PIK3CA mutation may be a molecular biomarker that predicts response to aspirin therapy. PIK3CA may also be a target of directed therapy in some clinical settings.

Last updated: 2020-07-24 14:53:48 UTC
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Tier 1
SMO
Variants
SMO W535L
Primary Sites
Brain, Infratentorial
Brain
Brain, Supratentorial
Tumor Types
Medulloblastoma
Interpretation

Some studies have demonstrated activity of sonic hedgehog pathway inhibitors in a subset of medulloblastomas harboring alterations in this pathway.

Last updated: 2017-01-20 03:30:12 UTC
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Tier 1
MDM2
Variants
MDM2 copy number gain
Primary Sites
Soft Tissue
Tumor Types
Liposarcoma
Interpretation

MDM2 encodes a nuclear-localized E3 ubiquitin ligase that may promote tumor formation by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. Overexpression or amplification of this locus has been detected in a variety of different cancers. MDM2 copy number gain has been shown to be useful in distinguishing dedifferentiated liposarcoma from spindle and pleomorphic sarcomas . The prognostic value of MDM2 copy number gain remains to be fully elucidated. Small molecular inhibitors of the MDM2:p53 axis are currently in early phase clinical trials for a number of malignancies.

Last updated: 2017-01-20 03:30:38 UTC
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Tier 1
MAP2K2
Variants
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

MAP2K2 mutations result in constitutive ERK phosphorylation and may be associated with higher resistance to MEK inhibitors. However these inhibitors are currently undergoing clinical trials and their efficacy and/or lack of toxicity has not yet been demonstrated.

Last updated: 2017-01-20 03:30:54 UTC
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Tier 1
MAP2K1
Variants
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

MAP2K1 mutations result in constitutive ERK phosphorylation and may be associated with higher resistance to MEK inhibitors. However these inhibitors are currently undergoing clinical trials and their efficacy and/or lack of toxicity has not yet been demonstrated.

Last updated: 2017-01-20 03:31:14 UTC
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Tier 1
MAP2K1
Variants
MAP2K1 C121S
Primary Sites
Blood
Bone Marrow
Lymph Node
Tumor Types
Hairy Cell Leukemia
Follicular Lymphoma
Langerhans Cell Histiocytosis
Interpretation

The p.C121S mutation has been associated with resistance to mutant BRAF inhibitors.

Last updated: 2017-01-20 03:31:52 UTC
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Tier 1
FGFR1
Variants
FGFR1 copy number gain
Primary Sites
Colon
Rectum
Gastroesophageal Junction
Esophagus
Peritoneum
Retroperitoneum
Stomach
Appendix
Tumor Types
Gastrointestinal Stromal Tumor
Interpretation

FGFR1 activating mutations may be associated with response to the multitargeted tyrosine kinase inhibitor pazopanib.

Last updated: 2017-01-20 03:32:36 UTC
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Tier 2
CEBPA
Variants
Primary Sites
Breast
Thyroid
Tumor Types
Medullary Carcinoma
Interpretation

Although CEBPA mutations have been described in AML, the significance of this mutation in this tumor is unclear.

Last updated: 2017-01-20 03:33:02 UTC
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Tier 2
CEBPA
Variants
CEBPA Q83*
Primary Sites
Breast
Thyroid
Tumor Types
Medullary Carcinoma
Interpretation

Although CEBPA mutations have been described in AML, the significance of this mutation in this tumor is unclear.

Last updated: 2017-01-20 03:33:15 UTC
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Tier 1
CDC73
Variants
Primary Sites
Parathyroid
Tumor Types
Carcinoma
Interpretation

CDC73 mutations have been previously reported in parathyroid tumors. However, it could be a germ line alteration.

Last updated: 2017-01-20 03:34:03 UTC
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Tier 1
BTK
Variants
BTK C481S
Primary Sites
Lymph Node
Blood
Bone Marrow
Tumor Types
Chronic Lymphocytic Leukemia
Mantle Cell Lymphoma
Interpretation

The BTK p.C481S variant has been previously reported to be associated with Ibrutinib resistance in patients with chronic lymphocytic leukemia.

Last updated: 2017-01-20 03:34:31 UTC
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Tier 1
AKT1
Variants
Primary Sites
Breast
Tumor Types
Adenocarcinoma
Interpretation

Activating mutations in AKT1 may be associated with sensitivity to AKT inhibitors.

Last updated: 2017-01-20 03:35:27 UTC
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Tier 1
PTCH1
Variants
Primary Sites
Skin
Tumor Types
Adenocarcinoma
Basal Cell Carcinoma
Squamous Cell Carcinoma
Small Cell Carcinoma
Interpretation

PTCH1 loss of function mutations are associated with Vismodegib sensitivity in basal cell carcinoma. However, the clinical significance in other tumor types is unknown.

Last updated: 2017-01-20 03:36:18 UTC
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Tier 1
PTCH1
Variants
PTCH1 W844C
Primary Sites
Skin
Tumor Types
Basal Cell Carcinoma
Interpretation

The W844C mutation is associated with resistance to Vismodegib in basal cell carcinoma.

Last updated: 2017-01-20 03:36:39 UTC
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Tier 1
MET
Variants
Primary Sites
Kidney
Tumor Types
Papillary Renal Cell Carcinoma
Interpretation

Activating somatic mutations in the tyrosine kinase domain of MET are found in about 10–15% of sporadic papillary renal cell carcinoma (pRCC). MET mutations are predominantly associated with Type 1 pRCC tumors. The responses to foretanib an oral inhibitor of MET and other tyrosine kinases including VEGFR2, have been described in patients with papillary renal cell cancer.

Last updated: 2017-01-20 03:37:19 UTC
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Tier 2
KRAS
Variants
KRAS G12V
KRAS G12D
KRAS G12C
KRAS G12S
KRAS G12R
KRAS G13D
KRAS G13C
KRAS G13S
KRAS G13R
KRAS G12A
Primary Sites
Stomach
Tumor Types
Adenocarcinoma
Interpretation

KRAS mutations are infrequent in gastric carcinomas and have been reported in approximately 6% of cases. Studies have shown no statistically significant difference in survival between KRAS-mutated and KRAS-non-mutated gastric carcinomas. However, one study showed a trend that the presence of a KRAS mutation was associated with better overall survival in gastric carcinoma patients. There is an increased frequency of KRAS mutations in gastric carcinomas with microsatellite instability. In gastric cancer, the predictive ability of KRAS has not been extensively studied, but a small study did not demonstrate an effect on survival in patients treated with an EGFR inhibitor.

Last updated: 2019-05-28 17:41:21 UTC
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Tier 1
KIT
Variants
Primary Sites
Brain
Brain, Infratentorial
Brain, Supratentorial
Tumor Types
Glioblastoma
Neuroblastoma
Astrocytoma, Anaplastic
Oligodendroglioma
Ependymoma
Ependymoma, Anaplastic
Interpretation

In AML, presence of exon 17 mutations in KIT may confer an adverse prognosis or increased relapse rate. However, its significance in brain tumors is yet to be determined.

Last updated: 2017-01-20 03:37:57 UTC
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Tier 1
KIT
Variants
Primary Sites
Kidney
Tumor Types
Renal Cell Carcinoma
Interpretation

In AML, presence of exon 17 mutations in KIT may confer an adverse prognosis or increased relapse rate. However, its significance in renal cancer is yet to be determined.

Last updated: 2017-01-20 03:38:15 UTC
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Tier 1
GNAQ
Variants
Primary Sites
Eye
Tumor Types
Melanoma
Interpretation

This gene is often mutated in uveal melanoma. A frequent mutation in GNAS/QNA11 (Q209) can promote disease progression. Combined mTOR/PI3K and MEK inhibition is showing promises in preclinical studies.

Last updated: 2017-01-20 03:38:46 UTC
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Tier 1
FGFR3
Variants
Primary Sites
Bladder
Ureter
Tumor Types
Urothelial Carcinoma
Interpretation

FGFR3 mutations may be associated with response to the multi-targeted tyrosine kinase inhibitor pazopanib.

Last updated: 2017-01-20 03:38:59 UTC
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Tier 1
FGFR2
Variants
Primary Sites
Kidney
Brain
Tumor Types
Renal Cell Carcinoma
Glioblastoma
Interpretation

FGFR2 mutation in a patient with oral squamous cell carcinoma was associated with response to the multitargeted tyrosine kinase inhibitor pazopanib. The clinical significance of this finding in this tumor type is unknown.

Last updated: 2017-01-20 03:39:23 UTC
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Tier 1
FGFR2
Variants
Primary Sites
Oral Cavity
Tumor Types
Squamous Cell Carcinoma
Interpretation

FGFR2 mutation in a patient with oral squamous cell carcinoma was associated with response to the multitargeted tyrosine kinase inhibitor pazopanib.

Last updated: 2017-01-20 03:39:38 UTC
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Tier 1
FGFR2
Variants
Primary Sites
Bladder
Ureter
Tumor Types
Urothelial Carcinoma
Interpretation

Although FGFR2 mutation in a patient with oral squamous cell carcinoma was reported to be associated with response to the multitargeted tyrosine kinase inhibitor pazopanib, FGFR2 mutations in bladder cancer are very rare. The clinical significance of this finding is unknown.

Last updated: 2017-01-20 03:39:54 UTC
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Tier 1
FGFR1
Variants
FGFR1 copy number gain
Primary Sites
Lung
Tumor Types
Squamous Cell Carcinoma
Interpretation

FGFR1 amplification is associated with poor survival in patients with resected squamous cell lung cancer. FGRF1 amplification may be associated with sensitivity to the multitargeted tyrosine kinase inhibitor pazopanib.

Last updated: 2017-01-20 03:40:24 UTC
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Tier 1
FGFR1
Variants
FGFR1 copy number gain
Primary Sites
Colon
Tumor Types
Adenocarcinoma
Interpretation

FGFR1 amplification may be associated with sensitivity to the multitargeted tyrosine kinase inhibitor pazopanib in some tumor types.

Last updated: 2017-01-20 03:40:39 UTC
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Tier 1
FGFR1
Variants
FGFR1 copy number gain
Primary Sites
Prostate
Tumor Types
Carcinoma
Adenocarcinoma
Small Cell Carcinoma
Neuroendocrine Carcinoma
Interpretation

The FGFR1 copy number gain is part of a large partial chrom 8 gain. The role of FGFR1 in prostate cancer is under study. FGRF1 amplification may be associated with sensitivity to pazopanib in some tumor types.

Last updated: 2017-01-20 03:40:57 UTC
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Tier 1
ERBB4
Variants
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

Melanomas with ERBB4 mutations may be associated with sensitivity to Lapatinib.

Last updated: 2017-01-20 03:41:12 UTC
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Tier 1
EGFR
Variants
EGFR copy number gain
Primary Sites
Colon
Rectum
Tumor Types
Carcinoma
Adenocarcinoma
Interpretation

In colorectal cancer, EGFR gene amplification is associated with sensitivity EGFR-targeted therapies, such as Erbitux and Vectibix.

Last updated: 2017-01-20 03:41:37 UTC
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Tier 1
CDKN2B
Variants
CDKN2B copy number loss
Primary Sites
Bladder
Tumor Types
Urothelial Carcinoma
Interpretation

The CDKN2B gene locus is altered in up to approximately 60% of bladder cancer, most commonly as a homozygous deletion, and frequently with concurrent deletion of the CDKN2A locus. CDKN2A/CDKN2B loss may be associated with increased sensitivity to CDK4/6 inhibitors. The efficacy and toxicity profiles of these inhibitors in the context of a variety of cancer types are currently under evaluation in clinical trials.

Last updated: 2017-01-20 03:42:19 UTC
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Tier 1
CDC73
Variants
Primary Sites
Parathyroid
Tumor Types
Interpretation

CDC73 mutations have been previously reported in parathyroid tumors.

Last updated: 2017-01-20 03:42:33 UTC
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Tier 1
BRCA2
Variants
BRCA2 any mutation
Primary Sites
Bladder
Ovary
Prostate
Tumor Types
Urothelial Carcinoma
Adenocarcinoma
Interpretation

Some mutations in BRCA2 may be associated with sensitivity to PARP inhibitors. The effect of this missense mutation is not entirely clear. Drug: Rucaparib Niraparib Olaparib

Last updated: 2018-04-06 15:08:46 UTC
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Tier 1
BRCA1
Variants
BRCA1 any mutation
Primary Sites
Breast
Ovary
Prostate
Tumor Types
Adenocarcinoma
Interpretation

Inactivating mutations in BRCA1 may be associated with sensitivity to PARP inhibitors. Drug Rucaparib Niraparib Olaparib

Last updated: 2018-04-18 14:26:36 UTC
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Tier 1
EML4
Variants
EML4-ALK rearrangement
Primary Sites
Lung
Tumor Types
Non-Small Cell Lung Carcinoma
Adenocarcinoma
Interpretation

The ALK gene encodes a receptor tyrosine kinase that is recurrently altered by chromosomal rearrangements in multiple malignancies, and the prevalence of oncogenic ALK fusions in lung adenocarcinoma is approximately 5%. The EML4-ALK fusion is known to be oncogenic. Crizotinib is a tyrosine kinase inhibitor that is FDA approved for treatment of ALK-fusion positive lung non-small lung carcinoma.

Last updated: 2019-12-30 23:08:04 UTC
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Tier 1
AKT3
Variants
Primary Sites
Blood
Bone Marrow
Skin
Kidney
Tumor Types
Chronic Myeloid Leukemia
Other Acute Leukemia
Melanoma
Clear Cell Renal Cell Carcinoma
Interpretation

AKT3 is closely related to AKT1. Activating mutations in AKT1 such as p.E17K may be associated with sensitivity to AKT inhibitors. AKT3 activating mutations might also confer sensitivity to AKT inhibitors, although the significance of this variant is uncertain.

Last updated: 2017-01-20 03:43:38 UTC
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Tier 1
AKT2
Variants
Primary Sites
Blood
Bone Marrow
Tumor Types
Chronic Myeloid Leukemia
Other Acute Leukemia
Interpretation

AKT2 is closely related to AKT1. Activating mutations in AKT1 such as p.E17K may be associated with sensitivity to AKT inhibitors. AKT2 activating mutations might also confer sensitivity to AKT inhibitors, although the significance of this variant is uncertain.

Last updated: 2017-01-20 03:44:03 UTC
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Tier 1
BRAF
Variants
BRAF codon(s) 594 any
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. BRAF mutations are present in approximately 50% to 60% of cutaneous melanomas and are also present at lower frequencies in other melanoma subtypes. A point mutation, D594G, is located in the kinase domain of BRAF. Mutations at residue D594 are believed to result in an impaired kinase activity. Correlation with other clinical and lab findings is necessary.

Last updated: 2017-01-20 03:45:28 UTC
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Tier 2
KRAS
Variants
KRAS L19F
Primary Sites
Colon
Tumor Types
Adenocarcinoma
Interpretation

KRAS is a gene that encodes one of the several proteins in the epidermal growth factor receptor (EGFR) signaling pathway that is important in the development and progression of cancer. KRAS can harbor oncogenic mutations that yield a constitutively active protein. Such mutations are found in approximately 30% to 50% of metastatic colorectal tumors and are common in other tumor types. KRAS L19F has been previously reported in colorectal cancers, but its oncogenic and transforming potential was reported to be significantly lower compared to codons 12 or 13 KRAS mutants. The predictive and prognostic significance of this specific mutation in KRAS needs further elucidation. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2017-01-30 21:47:53 UTC
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Tier 3
APC
Variants
APC I1307K
Primary Sites
Pancreas
Tumor Types
Adenocarcinoma
Interpretation

The APC gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. APC promotes rapid degradation of beta-catenin and participates in Wnt signaling as a negative regulator. APC is also involved in other processes including cell migration, cell adhesion, transcriptional activation and apoptosis. Germline defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. Pancreatic cancer is considered a low risk cancer, though it is observed in FAP families with higher incidence than the general populations. Somatic APC mutations have been reported in ~1% of pancreatic ductal adenocarcinomas (PDAC). Codon I1307 lies within a regulatory region of the APC protein mediated by ubiquitination. APC I1307K is associated with increased colorectal cancer risk by making the gene unstable and prone to acquire mutations during normal cell division. The germline APC I1307K gene mutation is most commonly found in people of Ashkenazi Jewish descent. Therefore, routine colorectal screening is very important in these individuals. The prognostic and therapeutic implications of APC mutations in PDAC remain to be fully elucidated. Correlation with other clinical and lab findings is recommended.

Last updated: 2017-01-30 21:57:13 UTC
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Tier 2
IDH1
Variants
IDH1 R132C
IDH1 codon(s) 132 any
Primary Sites
Colon
Tumor Types
Adenocarcinoma
Interpretation

IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies including AML, central nervous system and biliary tract. Strikingly, IDH1 mutations were rarely detected in the other solid tumor types. IDH1 mutation has been reported in up to 2% of colorectal adenocarcinomas. The clinical significance of this mutation with regards to response to anti-IDH1 therapy in colorectal cancer is unknown. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2018-04-18 18:23:31 UTC
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Tier 2
EGFR
Variants
EGFR V774M
Primary Sites
Brain
Tumor Types
Glioblastoma
Interpretation

EGFR mutations have been reported in up to 21% of glioblastoma tumors (GBM). In GBM, EGFR mutations typically cluster in the extracellular domain and include in-frame deletions and missense mutations. However, mutations (such as V774M) in the tyrosine kinase domain of EGFR have been previously reported in GBM. The clinical significance of this mutation with regards to response to TKI therapy in GBM needs further elucidation. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2017-02-03 21:49:47 UTC
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Tier 3
APC
Variants
Primary Sites
Ovary
Tumor Types
Interpretation

The APC gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. APC promotes rapid degradation of beta-catenin and participates in Wnt signaling as a negative regulator. APC is also involved in other processes including cell migration, cell adhesion, transcriptional activation and apoptosis. Germline defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. Somatic mutations in this gene may be observed in colorectal cancer (CRC), stomach cancer and desmoid tumors. Although APC mutations have been reported in ~2% of ovarian serous adenocarcinomas, further studies are needed to explore the clinical value of these mutations in ovarian cancers. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2017-02-06 20:00:54 UTC
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Tier 2
BRAF
Variants
BRAF N581S
Primary Sites
Small Intestine
Tumor Types
Adenocarcinoma
Interpretation

BRAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. BRAF mutations are infrequent in small intestinal adenocarcinoma, ranging from 1% to13% of reported cases. BRAF N581S mutation is located in the kinase domain and has been associated with intermediate kinase activity. Mutations in the kinase region of BRAF have been associated with resistance to anti-EGFR therapy in colorectal cancers. The prognostic and predictive significance of this specific BRAF mutation in small intestinal adenocarcinoma needs further elucidation. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2017-02-06 20:03:42 UTC
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Tier 1
ERBB2
Variants
ERBB2 copy number gain
Primary Sites
Breast
Tumor Types
Adenocarcinoma
Interpretation

In breast cancer, ERBB2 (HER2) amplification and over-expression are associated with sensitivity to anti-HER2 agents, such as Trastuzumab. Drug : Lapatinib + Trastuzumab, Pertuzumab + Trastuzumab, Ado-trastuzumab emtansine, Lapatinib, Trastuzumab,

Last updated: 2018-03-16 19:51:57 UTC
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Tier 1
CDK6
Variants
CDK6 copy number gain
Primary Sites
Breast
Brain
Tumor Types
Adenocarcinoma
Medulloblastoma
Interpretation

CDK (cyclin-dependent kinase) 4 and CDK6 are key players in cell cycle progression. In many human cancers, CDK6 is overactive, for example one third of medulloblastoma patients show upregulated CDK6. In 2015, FDA has granted an approval to CDK4/6 inhibitor palbociclib (Ibrance) as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer. However, per NCCN 2016 guideline for breast cancer, this treatment regime does not require the amplification of CDK4/6. Palbociclib, along with other CDK inhibitors, are actively under many other clinical trials targeting liposarcoma, various advanced solid tumors and hematologic malignancies.

Last updated: 2017-02-09 16:28:05 UTC
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Tier 1
CDK4
Variants
CDK4 copy number gain
Primary Sites
Breast
Soft Tissue
Tumor Types
Adenocarcinoma
Liposarcoma
Sarcoma
Interpretation

CDK (cyclin-dependent kinase) 4 and CDK6 are key players in cell cycle progression. In many human cancers, CDK4 is overactive, such as liposarcoma. In 2015, FDA has granted an approval to CDK4/6 inhibitor palbociclib (Ibrance) as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer. However, per NCCN 2016 guideline for breast cancer, this treatment regime does not require the amplification of CDK4/6. Palbociclib, along with other CDK inhibitors, are actively under many clinical trials targeting liposarcoma, various advanced solid tumors and hematologic malignancies.

Last updated: 2017-02-09 16:28:44 UTC
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Tier 2
AURKA
Variants
AURKA copy number gain
Primary Sites
Prostate
Breast
Colon
Pancreas
Ovary
Stomach
Tumor Types
Adenocarcinoma
Interpretation

Aurora A is a member of a family of mitotic serine/threonine kinases, playing an important role in cell proliferation. AURKA amplification may be associated with sensitivity to Aurora Kinase inhibitors. However these inhibitors are currently undergoing clinical trials and their efficacy and/or lack of toxicity has not yet been demonstrated.

Last updated: 2017-02-09 16:36:48 UTC
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Tier 3
CRKL
Variants
CRKL copy number gain
Primary Sites
Bladder
Tumor Types
Urothelial Carcinoma
Interpretation

In lung adenocarcinomas, CRKL amplification may be associated with resistance to EGFR-directed therapy (Cheung et al, 2011). However, its significance in urothelial cancer is yet to be determined.

Last updated: 2017-02-09 16:46:13 UTC
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Tier 2
CRKL
Variants
CRKL copy number gain
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

CRKL (Crk-like protein) is a substrate of the BCR-ABL tyrosine kinase, and plays a role in fibroblast transformation by BCR-ABL. It is potentially oncogenic. In lung adenocarcinomas, CRKL amplification may be associated with resistance to anti-EGFR therapy.

Last updated: 2017-02-09 17:17:18 UTC
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Tier 2
ERBB3
Variants
ERBB3 copy number gain
Primary Sites
Prostate
Bladder
Breast
Stomach
Ovary
Pancreas
Lung
Uterus
Tumor Types
Adenocarcinoma
Interpretation

This gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. Amplification of ERBB3 and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, non small cell lung cancer, endometrial cancer and breast tumors. Several ERBB3 inhibitors are under various clinical trials against different types of solid tumors, including non small cell lung cancer, breast cancer, ovarian cancer and gastric cancer.

Last updated: 2017-02-09 19:12:37 UTC
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Tier 2
CCND1
Variants
CCND1 copy number gain
Primary Sites
Bladder
Esophagus
Oral Cavity
Larynx
Bladder
Lung
Breast
Prostate
Ovary
Stomach
Pancreas
Tumor Types
Adenocarcinoma
Urothelial Carcinoma
Squamous Cell Carcinoma
Interpretation

The protein of CCND1 (Cyclin D 1) belongs to the highly conserved cyclin family, functioning as regulators of CDK kinases. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with tumor suppressor protein Rb and the expression of this gene is regulated positively by Rb. Amplification of this gene, which alters cell cycle progression, are observed frequently in a variety of tumors. Cyclin D1 and the mechanisms it regulates have the potential to be a therapeutic target for cancer drugs, including inhibition of Cyclin D1, induction of Cyclin D1 degradation, and inhibition of Cyclin D1/CDK 4/6 complex.

Last updated: 2017-02-09 20:02:30 UTC
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Tier 2
FGFR2
Variants
FGFR2 copy number gain
Primary Sites
Lung
Oral Cavity
Breast
Uterus
Stomach
Bladder
Testis
Ovary
Tumor Types
Squamous Cell Carcinoma
Urothelial Carcinoma
Adenocarcinoma
Germ Cell Tumor
Interpretation

Activation of FGFR protein family can lead to the activation of RAS-MAPK and PI3K-AKT pathways. Amplification of FGFR2 has been observed in lung adenocarcinoma, lung squamous cell carcinoma, endometrial carcinoma, urothelial carcinoma, germ cell tumor and breast cancers. Anti-FGFR2 agents are actively under multiple clinical trials against many types of solid tumor, including lung squamous cell carcinoma, gastric cancer, endometrial cancer, and cholangiocarcinoma. Germeline mutations in FGFR2 are also associated with multiple craniosynostosis syndromes.

Last updated: 2017-02-09 23:55:11 UTC
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Tier 2
KIT
Variants
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

KIT, also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117, is a growth factor receptor of the tyrosine kinase subclass III family, normally expressed in a variety of tissue types. Signaling through CD117 plays a role in cell survival, proliferation, and differentiation. Altered forms of this receptor may be associated with some types of cancers. Somatic mutations of KIT in lung adenocarcinoma are relatively rare, reported up to 3.3% of the cases. The predictive and prognostic significance of KIT mutations in lung adenocarcinomas needs further elucidation. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2017-02-10 15:53:25 UTC
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Tier 2
KIT
Variants
Primary Sites
Esophagus
Tumor Types
Adenocarcinoma
Interpretation

KIT, also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117, is a growth factor receptor of the tyrosine kinase subclass III family, normally expressed in a variety of tissue types. Signaling through CD117 plays a role in cell survival, proliferation, and differentiation. Altered forms of this receptor may be associated with some types of cancers. Somatic mutations of KIT in esophageal cancers are relatively rare, observed in up to 3.3% of the cases. The predictive and prognostic significance of KIT mutations in esophageal cancers needs further elucidation. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2017-02-21 13:37:50 UTC
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Tier 3
SMAD4
Variants
Primary Sites
Cervix
Tumor Types
Adenocarcinoma
Squamous Cell Carcinoma
Interpretation

SMAD4 is a tumor suppressor gene encoding an intracellular mediator in the transforming growth factor β (TGF β) signal transduction pathway. SMAD4 mutations have been observed in ~3% of cervical cancers. Functional inactivation of SMAD4 was found in 4 of 13 cervical squamous cancer cell lines, mostly due to homozygous loss. Loss of protein expression did not correlate with loss of heterozygosity and mutations in cervical squamous carcinomas; however, it was associated with poor disease-free and overall 5-year survival in one study. The predictive and prognostic significance of SMAD4 mutations in cervical cancers needs further elucidation. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2017-02-21 13:41:17 UTC
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Tier 3
SMAD4
Variants
Primary Sites
Bladder
Tumor Types
Urothelial Carcinoma
Interpretation

SMAD4 is a tumor suppressor gene encoding an intracellular mediator in the transforming growth factor β (TGF β) signal transduction pathway. SMAD4 mutations have been reported in up to 2% of urothelial carcinomas. The predictive and prognostic significance of SMAD4 mutations in urothelial carcinoma needs further elucidation. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2017-02-21 13:44:51 UTC
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Tier 2
IDH1
Variants
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

IDH1 is an enzyme localized to the cytoplasm and peroxisomes and involved in citrate metabolism. IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies including AML, central nervous system and biliary tract. Strikingly, IDH1 mutations were rarely detected in the other solid tumor types. IDH1 mutations have been reported in 1-2% of lung adenocarcinomas. The clinical significance of this mutation with regards to response to anti-IDH1 therapy in lung cancer is unknown. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2017-02-21 16:10:21 UTC
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Tier 2
ERBB2
Variants
ERBB2 L755S
ERBB2 L755P
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

ERBB2 encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. ERBB2 mutations have been reported in ~2-3% of lung adenocarcinomas. The majority of ERBB2 mutations are in-frame insertions in exon 20, which encodes part of the kinase domain; however, point mutations (L755S and G776C) have also been identified. Lung adenocarcinomas with ERBB2 mutations are mutually exclusive with EGFR, KRAS, ALK alterations and these variants are more frequent in patients who are never-smokers. Mutations in ERRB2 do not have an independent prognostic value in lung adenocarcinoma, according to a recent study. In vitro analyses have shown that ERBB2 L755P and L755S mutations are associated with constitutive kinase activation and resistance to lapatinib treatment. The predictive significance of ERBB2 mutations in lung adenocarcinomas needs further elucidation. Recommend correlation with other clinical and laboratory findings.

Last updated: 2017-02-21 16:15:52 UTC
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Tier 1
MET
Variants
MET copy number gain
Primary Sites
Stomach
Gastroesophageal Junction
Tumor Types
Adenocarcinoma
Interpretation

Amplification of MET, the hepatocyte growth factor receptor, is identified in 7% of Esophagus-Stomach cancer in recent TCGA study. Several studies investigated the relationship between MET amplification and expression with the clinical outcome in patients with gastric cancer, but yielded conflicting results. Multiple clinical trials of using anti-MET agent in the treatment of Esophagus-Stomach cancer are available.

Last updated: 2017-09-06 15:00:56 UTC
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Tier 1
ERBB2
Variants
ERBB2 S295F
Primary Sites
Bladder
Tumor Types
Adenocarcinoma
Interpretation

This mutation is located at extracellular domain. Patients with mutation of ERBB2 S310F, which is very close to S295 and also an extracellular domain, have been treated successfully with anti-HER agents (Jia et al, 2014; Vornicova et al, 2014). Although mutation at extracellular domain does not elevate HER2 protein level (negative for IHC), it might still activate HER2 protein or it’s downstream signaling.

Last updated: 2017-02-23 16:05:20 UTC
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Tier 2
PIK3CA
Variants
Primary Sites
Kidney
Tumor Types
Renal Cell Carcinoma
Interpretation

PIK3CA mutations activate the PI3K-PTEN-AKT pathway which is downstream from both the EGFR and RAS-RAF-MAPK pathways. The somatic mutations found thus far in PIK3CA are oncogenic, and the majority of them are clustered within exon 9 and 20 (helical and kinase domains). Activating mutations in PIK3CA are found in a wide variety of human cancers including up to 5% of renal cell carcinomas. The role of PIK3CA mutations as prognosticators of outcome or predictors of therapeutic response awaits further evaluation. Clinical trials are available for patients with PIK3CA mutated tumors.

Last updated: 2017-02-27 21:10:02 UTC
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Tier 2
CDKN2A
Variants
CDKN2A copy number loss
Primary Sites
Pancreas
Tumor Types
Adenocarcinoma
Interpretation

CDKN2A gene encodes p16 and functions as an important tumor suppressor in various human malignancies. Its activation prevents carcinogenesis via induction of cell growth arrest and senescence. The majority of the CDKN2A mutations span exon 2 and result in loss or decreased binding to CDK4/6, leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. Genetic alterations in CDKN2A have been reported in up to 41% of pancreatic adenocarcinomas (36% CNV loss and 5% SNV alterations). Few studies have suggested that CDKN2A is a causative gene in familial pancreatic cancer families. Germline mutations of CDKN2A among patients with pancreatic cancer are rare (<1%), with estimated penetrance of 58% and 39% for pancreatic cancer and melanoma, respectively. Multiple clinical trials are available for patients with CDKN2A deficient tumors. Predictive and prognostic significance of CDKN2A alterations in pancreatic cancer is not clear and correlation with other clinical and lab findings is necessary.

Last updated: 2017-03-02 23:18:55 UTC
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Tier 2
ERBB2
Variants
ERBB2 L869R
Primary Sites
Breast
Tumor Types
Adenocarcinoma
Interpretation

This mutation is recognized as gain of function mutation. Tumor with this mutation responds to neratinib, a type of TKI which is against HER2 and EGFR.

Last updated: 2018-12-13 21:07:39 UTC
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Tier 1
ERBB2
Variants
ERBB2 T798I
Primary Sites
Breast
Tumor Types
Adenocarcinoma
Interpretation

An acquired HER2 gatekeeper mutation induces resistance to neratinib in a patient with HER2 mutant-driven breast cancer

Last updated: 2017-03-08 21:32:18 UTC
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Tier 2
FOXL2
Variants
FOXL2 C134W
Primary Sites
Ovary
Tumor Types
Sex Cord Stromal Tumor
Interpretation

The FOXL2 gene resides on chromosome band 3q22.3 and encodes forkhead box protein L2, a forkhead-winged helix family transcription factor that is expressed in the eyelid and gonad during embryogenesis and actively maintains ovarian follicles during adulthood. A somatic missense mutation in FOXL2 (p.C134W; c.402C>G) is identified in 97% of adult granulosa cell tumor, and absent in other ovarian cancers. The prognosis and target treatment in regard of FOXL2 mutation is unknown.

Last updated: 2017-03-12 22:47:13 UTC
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Tier 2
BRAF
Variants
BRAF G464V
BRAF codon(s) 464 any
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. BRAF mutations are present in approximately 50% to 60% of cutaneous melanomas and are also present at lower frequencies in other melanoma subtypes. Mutations at protein residue G464 are rare in melanoma and have not been reported in previous sequencing studies. The G464V mutation results in an amino acid substitution within the highly conserved motif of the kinase domain. This specific mutation is a low frequency cancer-associated variant classified as an intermediate activity mutant that moderately increases ERK activation and can transform cells. The predictive significance of this mutation needs further study. Clinical correlation is recommended.

Last updated: 2017-03-15 20:54:24 UTC
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Tier 2
BRAF
Variants
BRAF codon(s) 594 any
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Interpretation

Somatic mutations in BRAF have been found in up to 10% of all NSCLC, more common in adenocarcinomas. D594 is a highly conserved residue within the kinase domain of BRAF and mutation of this residue appears to result in kinase inactivation. In vitro study has shown that kinase-dead BRAF forms a constitutive complex with CRAF in the presence of activated RAS leading to MEK and ERK signaling. The predictive and prognostic significance of this mutation needs further study. Clinical correlation is recommended.

Last updated: 2017-03-15 21:04:30 UTC
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Tier 1
KRAS
Variants
KRAS G13D
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

KRAS is a gene that encodes one of the several proteins in the epidermal growth factor receptor (EGFR) signaling pathway that is important in the development and progression of cancer. KRAS can harbor oncogenic mutations that yield a constitutively active protein. Such mutations are found in approximately 30% to 50% of metastatic colorectal tumors and are common in other tumor types. Mutations in the KRAS gene may indicate poor prognosis and poor drug response with therapies targeted to EGFR. The absence of a KRAS mutation predicts a greater likelihood of response to EGFR-targeted therapies and improved survival with such treatment. The relevant KRAS mutation is in one of five codons (12 13, 61, 117 or 146). The presence of KRAS mutations in codon 12, 13 or 61 is associated with a high likelihood of resistance to therapies targeting EGFR. However, preclinical studies have shown that G13D mutant cell lines have intermediate sensitivity to cetuximab and panitumumab. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2017-03-24 18:09:45 UTC
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Tier 1
EGFR
Variants
EGFR S768I
EGFR V769L
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Non-Small Cell Lung Carcinoma
Interpretation

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR tyrosine kinase inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. EGFR S768I (exon 20) occurs in 1–2% of EGFR mutant lung cancers and is often coincident with other EGFR mutations. S768I and V769L have previously been identified in the same NSCLC tumors. There are conflicting data regarding the sensitivity to EGFR-TKIs of tumors harboring S768I and V769L mutations. Correlation with other clinical and laboratory findings is necessary.

Last updated: 2017-04-10 18:14:01 UTC
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Tier 2
GNAS
Variants
GNAS codon(s) 201, 844 any
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

GNAS is a component of the heterotrimeric G-protein complex that has been shown to be mutated in 3-7% of colorectal cancers. Mutations at codon R201 of GNAS are typically activating mutations which have been described in various types of solid tumors. These mutations result in disruption of the intrinsic hydrolytic activity of Gsa, leading to constitutive activation. The clinical significance of these mutations in colorectal cancer remains to be established. Correlation with other clinical and laboratory findings is recommended.

Last updated: 2018-03-28 18:20:06 UTC
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Tier 3
MET
Variants
MET E168D
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

MET is a member of the receptor tyrosine kinase and proto-oncogene playing a major role in tumor development and metastasis. MET mutations have been reported in ~2% of colon cancers. MET E168D mutation is located in a conserved domain containing the ligand binding site. In vitro studies have shown that E168D may be associated with higher ligand affinity and higher susceptibility to c-Met inhibitors in lung cancer. The prognostic and predictive significance of MET mutations in colon cancer is not clear and correlation with other clinical and laboratory findings is necessary.

Last updated: 2017-04-10 19:03:06 UTC
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Tier 2
CDKN2A
Variants
CDKN2A V126D
Primary Sites
Skin
Tumor Types
Melanoma
Interpretation

CDKN2A gene functions as an important tumor suppressor via induction of cell growth arrest and senescence. Majority of the CDKN2A mutations result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. CDKN2A is a major high-risk susceptibility gene identified in melanoma. Somatic mutations of CDKN2A are reported in up to 19% and 20% of cutaneous and desmoplastic melanomas, respectively. Germline mutations have been reported in ~20-40% of families with melanoma. CDKN2A V126D mutation has been reported in numerous cases of familial melanoma and shown to be a loss-of-function mutation with reduced CDK4 binding. Correlation with other clinical and lab findings is necessary.

Last updated: 2017-04-10 19:10:58 UTC
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Tier 2
BRAF
Variants
BRAF codon(s) 594 any
Primary Sites
Small Intestine
Tumor Types
Adenocarcinoma
Interpretation

BRAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. BRAF mutations are infrequent in small intestinal adenocarcinoma, ranging from 1% to 13% of reported cases. D594 is a highly conserved residue within the kinase domain of BRAF and mutation of this residue appears to result in kinase inactivation. In vitro study has shown that kinase-dead BRAF forms a constitutive complex with CRAF in the presence of activated RAS leading to MEK and ERK signaling. The predictive and prognostic significance of this specific BRAF mutation in small intestinal adenocarcinoma needs further study. Results should be interpreted in conjunction with other laboratory and clinical findings.

Last updated: 2017-04-17 22:55:16 UTC
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Tier 3
MET
Variants
MET E168D
Primary Sites
Brain
Tumor Types
Glioblastoma
Astrocytoma, Anaplastic
Astrocytoma, Pilocytic
Interpretation

MET is a member of the receptor tyrosine kinase and proto-oncogene playing a major role in tumor development and metastasis. MET mutations have been reported in up to 3.3% of low-grade gliomas and 2.2% of glioblastomas. MET E168D mutation is located in a conserved domain containing the ligand binding site. In vitro studies have shown that E168D may be associated with higher ligand affinity and higher susceptibility to c-Met inhibitors in lung cancer. The predictive and prognostic significance of MET mutations in brain tumors is unclear and needs to be further studied. Correlation with other clinical and laboratory findings is recommended.

Last updated: 2017-04-17 22:58:40 UTC
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Tier 2
KRAS
Variants
Primary Sites
Brain
Tumor Types
Ganglioglioma
Interpretation

KRAS is a gene that encodes one of the several proteins in the epidermal growth factor receptor (EGFR) signaling pathway that is important in the development and progression of cancer. KRAS can harbor oncogenic mutations that yield a constitutively active protein. KRAS mutations have been reported in up to 1.6% of low-grade gliomas and in 1% of glioblastomas. KRAS mutations have not previously reported in ganglioglioma. The predictive and prognostic significance of KRAS mutations in ganglioglioma is unclear and needs to be further studied. Correlation with other clinical and laboratory findings is recommended.

Last updated: 2017-04-17 23:02:55 UTC
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Tier 2
APC
Variants
APC any missense
APC any nonsense
APC any frameshift
Primary Sites