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BRAF
Variants
VariantGeneTypeCOSMIC IDDNA Change (Coding Nucleotide)Exon
BRAF D594GBRAFmissenseCOSM4671781A>G15
BRAF G469EBRAFmissenseCOSM4611406G>A11
BRAF L597VBRAFmissenseCOSM4701789C>G15
BRAF V600DBRAFmissenseCOSM4771799_1800TG>AT15
BRAF V600EBRAFmissenseCOSM4761799T>A15
BRAF V600KBRAFmissenseCOSM4731798_1799GT>AA15
BRAF V600RBRAFmissenseCOSM4741798_1799GT>AG15
BRAF codon(s) 600 anyBRAFany15
BRAF G469ABRAFmissense11
BRAF codon(s) 469 anyBRAFany11
BRAF G464VBRAFmissense11
BRAF codon(s) 464 anyBRAFany11
BRAF K601EBRAFmissense15
BRAF codon(s) 601 anyBRAFany15
BRAF D594EBRAFmissense15
BRAF codon(s) 594 anyBRAFany15
BRAF T599_V600insTBRAFinsertion15
BRAF T599_V600insVBRAFinsertion1795GTTins 15
BRAF F595SBRAFmissenseCOSM11231784T>C15
BRAF L597RBRAFmissenseCOSM4711790T>G15
BRAF G466VBRAFmissenseCOSM4511397G>T11
BRAF N581SBRAFmissenseCOSM4621742A>G
BRAF E586KBRAFmissenseCOSM4631756G>A15
BRAF V600MBRAFmissenseCOSM11301798G>A15
BRAF D594NBRAFmissenseCOSM276391780G>A15
BRAF G469VBRAFmissenseCOSM4591406G>T11
BRAF L597QBRAFmissenseCOSM11251790T>A15
BRAF L597SBRAFmissenseCOSM11261789_1790CT>TC15
BRAF V600GBRAFmissenseCOSM61371799T>G15
BRAF G596CBRAFmissense
BRAF copy number gainBRAFCNV
BRAF copy number lossBRAFCNV
BRAF any mutationBRAFany
BRAF G469RBRAFmissense11
BRAF G466RBRAFmissense11
BRAF F468SBRAFmissense11
BRAF N581IBRAFmissense14, 15
BRAF V590IBRAFmissense15

Interpretations

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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
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 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 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 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 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 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 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 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 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
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 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
Read More
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 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 1
BRAF
Variants
BRAF V600E
Primary Sites
Brain
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 typically mutually exclusive but may occasionally coexist. 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. Treatment with the BRAF inhibitor vemurafenib has been reported to result in disease stabilization in a patient with a papillary craniopharyngioma with a BRAF V600E mutation.

Last updated: 2020-07-24 14:53:53 UTC
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Tier 2
BRAF
Variants
BRAF copy number gain
BRAF copy number loss
Primary Sites
Adrenal Gland
Anus
Ampulla (Pancreaticobiliary Duct)
Appendix
Bladder
Blood
Bone
Bone Marrow
Brain
Breast
Spinal Cord
Cervix
Chest Wall
Colon
Endometrium
Esophagus
Eye
Fallopian Tube
Fibroadipose Tissue
Gall Bladder
Kidney
Larynx
Liver
Lung
Lymph Node
Nasal Cavity
Oral Cavity
Ovary
Pancreas
Parathyroid
Penis
Peripheral Nervous System
Peritoneum
Pharynx
Pituitary
Placenta
Pleura
Prostate
Retroperitoneum
Salivary Gland
Seminal Vesicle
Skeletal Muscle
Skin
Small Intestine
Soft Tissue
Spleen
Stomach
Testis
Thymus
Thyroid
Tonsil
Unknown
Ureter
Uterus
Vagina
Rectum
Cartilage
Blood Vessel
Buccal Swab
Heart
Trachea
Salivary Duct
Spermatic Cord
Vulva
Brain, Infratentorial
Brain, Supratentorial
Gastroesophageal Junction
Sellar
Suprasellar
Peritoneal fluid
Pleural Fluid
Tongue
Tumor Types
Acinar Cell Carcinoma
Acinic Cell Carcinoma
Adenocarcinoma
Adenoid Cystic Carcinoma
Adenosarcoma
Ameloblastic Tumor
Anaplastic Large Cell Lymphoma
Angioimmunoblastic T-Cell Lymphoma
Angiomatoid Fibrous Histiocytoma
Angiomatosis
Angiomyolipoma
Angiosarcoma
Astrocytoma, Anaplastic
Basal Cell Carcinoma
Burkitt Lymphoma
Carcinoid Tumor
Carcinoma
Carcinosarcoma
Cholangiocarcinoma
Chondrosarcoma
Chordoma
Choriocarcinoma
Chromophobe Renal Cell Carcinoma
Chronic Lymphocytic Leukemia
Classical Hodgkin Lymphoma
Clear Cell Carcinoma
Clear Cell Renal Cell Carcinoma
Craniopharyngioma
Dermatofibrosarcoma
Desmoplastic Small Round Cell Tumor
Diffuse Large B Cell Lymphoma
Ductal Carcinoma
Ependymoma
Ewing Sarcoma
Fibromatosis
Follicular Carcinoma
Follicular Lymphoma
Gastrointestinal Stromal Tumor
Germ Cell Tumor
Giant Cell Tumor
Glioblastoma
Glomus Tumor
Granular Cell Tumor
Hairy Cell Leukemia
Hemangioendothelioma
Hepatocellular Carcinoma
Invasive Ductal Carcinoma
Kaposi Sarcoma
Leiomyoma
Leiomyosarcoma
Lipoma
Liposarcoma
Lobular Carcinoma
Lymphoplasmacytic Lymphoma
Malignant Mullerian Mixed Tumor
Mantle Cell Lymphoma
Marginal Zone B Cell Lymphoma
Medullary Carcinoma
Medulloblastoma
Melanoma
Meningioma
Merkel Cell Carcinoma
Mesothelioma
Mucinous Adenocarcinoma
Mucinous Tumors of Ovary
Mucoepidermoid Carcinoma
Myxofibrosarcoma
Nasopharyngeal Carcinoma
Neuroblastoma
Neuroendocrine Carcinoma
Neuroendocrine Neoplasm
NK Cell Lymphoproliferative Disorder
NLPHL
Non-Small Cell Lung Carcinoma
Oligodendroglioma
Osteosarcoma
Papillary Carcinoma
Papillary Renal Cell Carcinoma
Peripheral T Cell Lymphoma
Pheochromocytoma
Plasma Cell Disorder
Post-Transplant Lymphoproliferative Disorder
Primitive Neuroectodermal Tumor
Renal Cell Carcinoma
Reninoma
Retinoblastoma
Rhabdomyosarcoma
Sarcoma
Schwannoma
Serous Carcinoma
Sex Cord Stromal Tumor
Small Cell Carcinoma
Solid Pseudopapillary Tumor of Pancreas
Spindle Cell Neoplasm
Squamous Cell Carcinoma
T Cell Lymphoproliferative Disorder
T-Cell LGL Leukemia
Thymic Carcinoma
Thymoma
Urothelial Carcinoma
Tumors of Peripheral Nerves
Unknown
Wilms Tumor
Ependymoma, Anaplastic
Astrocytoma, Pilocytic
Ganglioglioma
Neuroepithelial Neoplasm, NOS
Pleomorphic Carcinoma
Solitary Fibrous Tumor
Neuroepithelial neoplasm, high grade
Astrocytoma, NOS
Astrocytoma, Diffusely Infiltrating
Diffuse Midline Glioma
Infiltrating Glioma, NOS
Intraductal Papillary Mucinous Neoplasm (IPMN)
Lymphadenopathy
Lymphocytosis, Symptomatic
Monoclonal Gammopathy
Mucinous or Serous Cystic Neoplasms of Pancreas
Mycosis Fungoides, Unspecified Site
Oligodendroglioma, Anaplastic
Pleomorphic Xanthoastrocytoma
Rash and Other Nonspecific Skin Eruption
Hurthle Cell Carcinoma
High Grade Glioma
Undifferentiated Sarcoma
Glioma
Interpretation

This gene is a known cancer gene.

Last updated: 2019-08-28 14:53:57 UTC
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Tier 2
BRAF
Variants
BRAF any mutation
Primary Sites
Adrenal Gland
Anus
Ampulla (Pancreaticobiliary Duct)
Appendix
Bladder
Blood
Bone
Bone Marrow
Brain
Breast
Spinal Cord
Cervix
Chest Wall
Colon
Endometrium
Esophagus
Eye
Fallopian Tube
Fibroadipose Tissue
Gall Bladder
Kidney
Larynx
Liver
Lung
Lymph Node
Nasal Cavity
Oral Cavity
Ovary
Pancreas
Parathyroid
Penis
Peripheral Nervous System
Peritoneum
Pharynx
Pituitary
Placenta
Pleura
Prostate
Retroperitoneum
Salivary Gland
Seminal Vesicle
Skeletal Muscle
Skin
Small Intestine
Soft Tissue
Spleen
Stomach
Testis
Thymus
Thyroid
Tonsil
Unknown
Ureter
Uterus
Vagina
Rectum
Cartilage
Blood Vessel
Buccal Swab
Heart
Trachea
Salivary Duct
Spermatic Cord
Vulva
Brain, Infratentorial
Brain, Supratentorial
Gastroesophageal Junction
Sellar
Suprasellar
Peritoneal fluid
Pleural Fluid
Tongue
Tumor Types
Acinar Cell Carcinoma
Acinic Cell Carcinoma
Adenocarcinoma
Adenoid Cystic Carcinoma
Adenosarcoma
Ameloblastic Tumor
Anaplastic Large Cell Lymphoma
Angioimmunoblastic T-Cell Lymphoma
Angiomatoid Fibrous Histiocytoma
Angiomatosis
Angiomyolipoma
Angiosarcoma
Astrocytoma, Anaplastic
Basal Cell Carcinoma
Burkitt Lymphoma
Carcinoid Tumor
Carcinoma
Carcinosarcoma
Cholangiocarcinoma
Chondrosarcoma
Chordoma
Choriocarcinoma
Chromophobe Renal Cell Carcinoma
Classical Hodgkin Lymphoma
Clear Cell Carcinoma
Clear Cell Renal Cell Carcinoma
Craniopharyngioma
Dermatofibrosarcoma
Desmoplastic Small Round Cell Tumor
Ductal Carcinoma
Ependymoma
Ewing Sarcoma
Fibromatosis
Follicular Carcinoma
Follicular Lymphoma
Gastrointestinal Stromal Tumor
Germ Cell Tumor
Giant Cell Tumor
Glioblastoma
Glomus Tumor
Granular Cell Tumor
Hairy Cell Leukemia
Hemangioendothelioma
Hepatocellular Carcinoma
Invasive Ductal Carcinoma
Kaposi Sarcoma
Leiomyoma
Leiomyosarcoma
Lipoma
Liposarcoma
Lobular Carcinoma
Lymphoplasmacytic Lymphoma
Malignant Mullerian Mixed Tumor
Mantle Cell Lymphoma
Marginal Zone B Cell Lymphoma
Medullary Carcinoma
Medulloblastoma
Melanoma
Meningioma
Merkel Cell Carcinoma
Mesothelioma
Mucinous Adenocarcinoma
Mucinous Tumors of Ovary
Mucoepidermoid Carcinoma
Myxofibrosarcoma
Nasopharyngeal Carcinoma
Neuroblastoma
Neuroendocrine Carcinoma
Neuroendocrine Neoplasm
NK Cell Lymphoproliferative Disorder
NLPHL
Non-Small Cell Lung Carcinoma
Oligodendroglioma
Osteosarcoma
Papillary Carcinoma
Papillary Renal Cell Carcinoma
Peripheral T Cell Lymphoma
Pheochromocytoma
Plasma Cell Disorder
Post-Transplant Lymphoproliferative Disorder
Primitive Neuroectodermal Tumor
Renal Cell Carcinoma
Reninoma
Retinoblastoma
Rhabdomyosarcoma
Sarcoma
Schwannoma
Serous Carcinoma
Sex Cord Stromal Tumor
Small Cell Carcinoma
Solid Pseudopapillary Tumor of Pancreas
Spindle Cell Neoplasm
Squamous Cell Carcinoma
T Cell Lymphoproliferative Disorder
T-Cell LGL Leukemia
Thymic Carcinoma
Thymoma
Urothelial Carcinoma
Tumors of Peripheral Nerves
Unknown
Wilms Tumor
Ependymoma, Anaplastic
Astrocytoma, Pilocytic
Ganglioglioma
Neuroepithelial Neoplasm, NOS
Pleomorphic Carcinoma
Solitary Fibrous Tumor
Neuroepithelial neoplasm, high grade
Astrocytoma, NOS
Astrocytoma, Diffusely Infiltrating
Diffuse Midline Glioma
Infiltrating Glioma, NOS
Intraductal Papillary Mucinous Neoplasm (IPMN)
Lymphadenopathy
Lymphocytosis, Symptomatic
Monoclonal Gammopathy
Mucinous or Serous Cystic Neoplasms of Pancreas
Mycosis Fungoides, Unspecified Site
Oligodendroglioma, Anaplastic
Pleomorphic Xanthoastrocytoma
Rash and Other Nonspecific Skin Eruption
Hurthle Cell Carcinoma
High Grade Glioma
Undifferentiated Sarcoma
Glioma
Interpretation

This gene is a known cancer gene.

Last updated: 2019-08-28 14:53:58 UTC
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Tier 2
BRAF
Variants
BRAF V600E
Primary Sites
Kidney
Bladder
Ureter
Unknown
Tumor Types
Urothelial Carcinoma
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 V600E lies within the activation segment of the kinase domain of the BRAF protein and confers a gain of function. BRAF mutations are infrequent in urothelial carcinoma and are identified in 3-5% of cases. Various BRAF inhibitors (Vemurafenib, Dabrafenib) have been FDA approved for therapy for some tumor types in certain settings. The use of BRAF inhibitors in a number of other cancer types harboring BRAF V600E mutations are under investigation (clinicaltrials.gov). The clinicopathologic effects of BRAF in urothelial carcinoma remains to be fully elucidated.

Last updated: 2018-03-06 17:57:39 UTC
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Tier 1
BRAF
Variants
BRAF G469R
Primary Sites
Skin
Tumor Types
Melanoma
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 present in approximately 50% to 60% of cutaneous melanomas and are also present at lower frequencies in other melanoma subtypes. The G469R variant accounts for less than 1% of mutations overall in melanoma; however, it has been shown to account for 13% of non-V600E BRAF mutations in a study of advanced melanoma cases. The G469R mutation results in an amino acid substitution at position 469 in BRAF and occurs within the highly conserved motif of the kinase domain. Amino acid substitutions at this positon have been shown to retain variable levels of kinase activity compared to the normal BRAF. The effect of this mutation (p.G469R) on the kinase activity of BRAF is unknown. Correlation with other clinical and lab findings is recommended.

Last updated: 2018-03-06 18:02:25 UTC
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Tier 2
BRAF
Variants
BRAF G469A
Primary Sites
Skin
Tumor Types
Squamous Cell Carcinoma
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 10% of cutaneous squamous cell carcinomas harbor somatic mutations in BRAF. The G469A mutation in exon 11 results in an amino acid substitution at position 469 in BRAF, which occurs in the highly conserved motif of the kinase domain. Most mutant BRAF proteins, such as G469A, have increased kinase activity and are transforming in vitro. Though BRAF mutations and targeted therapies have been have been studied in other solid tumors, the predicative and prognostic significant in cutaneous squamous cell carcinoma is unclear and needs to be further investigated.

Last updated: 2018-03-12 15:41:26 UTC
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Tier 2
BRAF
Variants
BRAF V600E
Primary Sites
Gall Bladder
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. The hotspot for mutations in BRAF is at codon Val600 and these are activating mutations. The most common activating mutation is p.Val600Glu(V600E). BRAF mutation frequencies are highly controversial in biliary tract cancers ranging from 0 to 33% for BRAF V600E. As most studies with high BRAF mutation rates were performed on European cohorts, this has raised the question of whether these discordant results represent a regional difference in the genetics of biliary tract cancer. In large cohort of biliary tract cancers including intrahepatic cholangiocarcinomas, extrahepatic cholangiocarcinomas, and adenocarcinomas of the gallbladder, BRAF V600E mutations were only rarely found in intrahepatic cholangiocarcinomas and were not identified in any cases of gallbladder adenocarcinoma. The clinicopathologic significance of BRAF V600E remains to be further elucidated in adenocarcinoma of the gallbladder. Various BRAF inhibitors (Vemurafenib, Dabrafenib) have been FDA approved for therapy for some tumor types in certain settings. These results should be interpreted in the clinical and radiographic context.

Last updated: 2018-03-30 16:12:50 UTC
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Tier 1
BRAF
Variants
BRAF L597Q
Primary Sites
Unknown
Tumor Types
Melanoma
Interpretation

Drug: Trametinib BGB659

Last updated: 2018-04-06 14:55:28 UTC
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Tier 1
BRAF
Variants
BRAF K601E
BRAF codon(s) 601 any
Primary Sites
Unknown
Tumor Types
Melanoma
Interpretation

Drug: Trametinib

Last updated: 2018-04-06 15:09:24 UTC
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Tier 1
BRAF
Variants
BRAF codon(s) 469 any
BRAF G469V
Primary Sites
Unknown
Tumor Types
Melanoma
Interpretation

DRUG: Trametinib

Last updated: 2018-04-06 15:10:23 UTC
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Tier 1
BRAF
Variants
BRAF D594N
Primary Sites
Unknown
Tumor Types
Melanoma
Interpretation

Trametinib

Last updated: 2018-04-06 15:11:17 UTC
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Tier 1
BRAF
Variants
BRAF V600G
Primary Sites
Unknown
Tumor Types
Melanoma
Interpretation

Vemurafenib Dabrafenib Dabrafenib + Trametinib Vemurafenib + Cobimetinib

Last updated: 2018-04-06 15:11:42 UTC
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Tier 1
BRAF
Variants
BRAF V600G
Primary Sites
Lung
Tumor Types
Non-Small Cell Lung Carcinoma
Interpretation

Vemurafenib Dabrafenib Dabrafenib + Trametinib

Last updated: 2018-04-06 15:16:54 UTC
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Tier 1
BRAF
Variants
BRAF V600D
Primary Sites
Unknown
Tumor Types
Langerhans Cell Histiocytosis
Interpretation

Vemurafenib

Last updated: 2018-04-06 15:19:38 UTC
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Tier 1
BRAF
Variants
BRAF V600D
BRAF codon(s) 600 any
Primary Sites
Unknown
Tumor Types
Melanoma
Interpretation

Drug Vemurafenib Dabrafenib Dabrafenib + Trametinib Vemurafenib + Cobimetinib

Last updated: 2018-04-06 15:22:28 UTC
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Tier 1
BRAF
Variants
BRAF codon(s) 600 any
BRAF V600G
Primary Sites
Unknown
Tumor Types
Langerhans Cell Histiocytosis
Interpretation

Vemurafenib

Last updated: 2018-04-06 15:37:37 UTC
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Tier 1
BRAF
Variants
BRAF V600D
Primary Sites
Lung
Tumor Types
Non-Small Cell Lung Carcinoma
Interpretation

Vemurafenib Dabrafenib Dabrafenib + Trametinib

Last updated: 2018-04-06 15:38:31 UTC
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Tier 1
BRAF
Variants
BRAF G469A
Primary Sites
Unknown
Tumor Types
Melanoma
Interpretation

DRUG: Trametinib

Last updated: 2018-04-06 15:39:25 UTC
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Tier 1
BRAF
Variants
BRAF K601E
Primary Sites
Blood
Bone Marrow
Tumor Types
Chronic Lymphocytic Leukemia
Interpretation

RAS/RAF path mutation has been identified in 5-9 % of CLL patients. 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: 2018-04-18 14:42:13 UTC
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Tier 1
BRAF
Variants
BRAF V600K
Primary Sites
Unknown
Tumor Types
Melanoma
Interpretation

Vemurafenib Dabrafenib Dabrafenib + Trametinib Vemurafenib + Cobimetinib Trametinib

Last updated: 2018-04-18 14:48:13 UTC
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Tier 1
BRAF
Variants
BRAF G596C
Primary Sites
Unknown
Tumor Types
Melanoma
Interpretation

Drug: Trametinib

Last updated: 2018-04-18 14:48:24 UTC
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Tier 1
BRAF
Variants
BRAF codon(s) 600 any
BRAF V600M
Primary Sites
Colon
Lung
Tumor Types
Melanoma
Langerhans Cell Histiocytosis
Non-Small Cell Lung Carcinoma
Interpretation

Vemurafenib Dabrafenib Dabrafenib + Trametinib Vemurafenib + Cobimetinib Vemurafenib + Panitumumab Encorafenib + Binimetinib + Cetuximab Radiation + Trametinib + Fluorouracil

Last updated: 2018-04-18 14:48:35 UTC
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Tier 1
BRAF
Variants
BRAF L597S
Primary Sites
Unknown
Tumor Types
Melanoma
Interpretation

Trametinib

Last updated: 2018-04-18 14:48:44 UTC
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Tier 2
BRAF
Variants
BRAF G466R
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 G466R mutation results in an amino acid substitution within the kinase domain of BRAF. Unlike other mutant BRAF proteins, G466R shows decreased kinase activity, however, it also causes paradoxically activation Erk signaling in cell culture Therapeutic implications of BRAF inhibitors in patients with this mutation need to be fully elucidated.

Last updated: 2018-04-18 18:23:55 UTC
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Tier 2
BRAF
Variants
BRAF G469V
Primary Sites
Colon
Rectum
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 G469V 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: 2018-04-18 18:24:08 UTC
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Tier 2
BRAF
Variants
BRAF F468S
Primary Sites
Thyroid
Tumor Types
Papillary Carcinoma
Interpretation

BRAF is part of the mitogen-activated protein kinase (MAPK) signaling pathway and is frequently mutated in papillary thyroid carcinoma (PTC). The BRAF V600E-like PTC's (BVL) and the RAS-like PTC (RL-PTC) are fundamentally different in their genomic, epigenomic, and proteomic profiles. The BRAF V600E mutation in Exon 15 is the most common BRAF mutation has been reported in 45% of patients with PTC. BRAF F468S is a rare somatic variant in Exon 11 and is located in the tyrosine kinase domain of the BRAF protein. The clinicopathologic effects of this variant as a somatic mutation in cancer has not been established in the literature. However, a mutation at the same location, F468C, has been shown to be a gain of function mutation. This variant has also been previously reported as a pathogenic germline variant in ClinVar associated with Cardio-facio-cutaneous syndrome. These results should be interpreted in the clinical context.

Last updated: 2018-05-02 20:00:05 UTC
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Tier 2
BRAF
Variants
BRAF G466V
Primary Sites
Colon
Rectum
Tumor Types
Adenocarcinoma
Interpretation

BRAF is part of the mitogen-activated protein kinase (MAPK) signaling pathway. BRAF G466V is a missense mutation which impairs BRAF kinase activity but paradoxically activates MEK and ERK through transactivation of c-RAF. This variant is associated with decreased cell proliferation and cell viability as compared to wild-type BRAF. This variant is a rare BRAF mutation and accounts for < 1% of BRAF mutations in colorectal adenocarcinoma. A single preclinical study of BRAF G466V in colon cancer demonstrated sensitivity to anti-EGFR tyrosine kinase therapy (cetuximab) and a MEK inhibitor (trametinib), however, there was no benefit seen with the RAF inhibitor vermurafinib. The clinicopathologic significance of BRAF G466V remains to be fully elucidated.

Last updated: 2018-05-16 16:44:53 UTC
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Tier 2
BRAF
Variants
BRAF K601E
Primary Sites
Kidney
Ureter
Bladder
Tumor Types
Urothelial Carcinoma
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. 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. BRAF mutations are infrequent in urothelial carcinoma and are identified in 3-5% of cases. Preclinical studies are investigating the use of MEK and RAS inhibitors in BRAF K601E mutant cell lines. The clinicopathologic effects of BRAF in this cancer type remain to be fully elucidated.

Last updated: 2018-05-24 20:14:52 UTC
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Tier 1
BRAF
Variants
BRAF V600D
BRAF V600E
BRAF V600K
BRAF V600R
BRAF codon(s) 600 any
Primary Sites
Blood
Bone Marrow
Tumor Types
Hairy Cell Leukemia
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. Some types of Hairy Cell Leukemia (eg, Hairy Cell Leukemia-Variant, Hairy Cell Leukemia with IgHV4-34 rearrangement) are negative for BRAF V600E mutation and may have MAP2K1 mutations. 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). B-Raf inhibitors(eg, Vemurafenib) have been FDA approved for therapy for various tumor types and have been used in Hairy Cell Leukemia in some clinical settings, including in combination with other therapy.

Last updated: 2018-11-12 20:40:47 UTC
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Tier 2
BRAF
Variants
BRAF V600E
Primary Sites
Pancreas
Tumor Types
Adenocarcinoma
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. 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). It has been found that BRAF V600E has a mutation frequency of 2% in pancreatic cancer. A small study showed that no BRAF mutations were present in cases without KRAS mutations and in the few cases with BRAF mutations, a KRAS mutation was also present.

Last updated: 2019-01-22 18:26:32 UTC
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Tier 2
BRAF
Variants
BRAF V600E
Primary Sites
Lung
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. The hotspot for mutations in BRAF is at codon Val600 and these are activating mutations. The most common activating mutation is p.Val600Glu(V600E). Activating BRAF(V600E) (Val600Glu) mutations have been identified in approximately 1-2% of lung adenocarcinomas. Various BRAF inhibitors (Vemurafenib, Dabrafenib, and Trametinib) have been FDA approved for therapy for some tumor types in certain clinical settings. Of note, Dabrafenib and Trametinib are approved for metastatic non-small cell lung cancer (NSCLC) harboring BRAF V600E mutations.

Last updated: 2019-01-22 18:29:57 UTC
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Tier 2
BRAF
Variants
BRAF N581I
Primary Sites
Rectum
Tumor Types
Adenocarcinoma
Interpretation

BRAF is a serine/threonine kinase that plays a key role in the regulation of the mitogen-activated protein kinase (MAPK) cascade. Genetic alterations in BRAF are found in a large percentage of melanomas, thyroid cancers and histiocytic neoplasms as well as a small fraction of lung and colorectal cancers. Somatic mutations in BRAF have been found in up to 10% of all NSCLC, more common in adenocarcinomas. Genetic alterations of BRAF have been identified in 9% of lung adenocarcinomas. BRAF N581I lies within the protein kinase domain of the Braf protein (UniProt.org). N581I results in low Braf kinase activity and Ras-dependent activation of Erk signaling in cell culture but, induces similar cell proliferation and cell viability as wild-type Braf. The BRAF N581I mutation is known to be oncogenic.

Last updated: 2019-01-22 18:34:26 UTC
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Tier 2
BRAF
Variants
BRAF E586K
Primary Sites
Rectum
Tumor Types
Adenocarcinoma
Interpretation

BRAF is a serine/threonine kinase that plays a key role in the regulation of the mitogen-activated protein kinase (MAPK) cascade. Genetic alterations in BRAF are found in a large percentage of melanomas, thyroid cancers and histiocytic neoplasms as well as a small fraction of lung and colorectal cancers. Somatic mutations in BRAF have been found in up to 10% of all NSCLC, more common in adenocarcinomas. Genetic alterations of BRAF have been identified in 9% of lung adenocarcinomas. E586 is located within the kinase domain of BRAF and E586K mutation has been shown to result in increased kinase activity. The BRAF E586K mutation is likely oncogenic although the predictive and prognostic significance of this mutation needs further study. Correlation with other laboratory and clinical findings is recommended.

Last updated: 2019-01-22 18:34:45 UTC
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Tier 1
BRAF
Variants
BRAF V600E
Primary Sites
Thyroid
Tumor Types
Carcinoma
Interpretation

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, which comprise 80 % of all thyroid cancers. 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 thyroid neoplasms, or nodular goiters. Anaplastic thyroid carcinomas are rare, highly aggressive, undifferentiated tumors that comprise 1% to 2% of all thyroid cancers in the United States. Well-differentiated papillary thyroid cancer, in which BRAF V600 mutations are an early and common driver mutation, precedes or coexists with approximately 50% of anaplastic thyroid carcinomas. Between 20% and 50% of anaplastic thyroid carcinomas harbor activating BRAF V600 mutations, with unknown prognostic significance. The possible prognostic impact of BRAF V600E mutations in carcinoma of the thyroid continues to be studied.

Last updated: 2019-05-23 22:43:59 UTC
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Tier 2
BRAF
Variants
BRAF V600E
Primary Sites
Larynx
Oral Cavity
Tumor Types
Squamous Cell 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. Mutations of B-RAF have been described in <2% of head and neck squamous cell carcinomas. The hotspot for mutations in BRAF is at codon Val600 and the most common one is p.Val600Glu (V600E). Various B-RAF inhibitors have been FDA approved for cancer therapy in certain settings.

Last updated: 2019-01-22 18:51:59 UTC
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Tier 3
BRAF
Variants
BRAF V590I
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. The BRAF V590I variant lies within the protein kinase domain of the Braf protein, has not been biochemically characterized, but results in similar cell proliferation and viability levels to wild-type Braf in culture (PMID: 29533785), and therefore is predicted to have no effect on Braf protein function, but its oncogenic potential has not been characterized. Clinical correlation is recommended.

Last updated: 2019-03-11 16:59:32 UTC
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Tier 2
BRAF
Variants
BRAF D594G
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.While clinical trials targeting BRAF-mutant NSCLC have mostly focused on patients with V600E-mutant disease, in vitro studies suggests potential sensitivity to targeted agents in cell lines with inactivating BRAF non-V600 mutations. However, established clinical activity of targeted BRAF and MEK inhibition in patients with these mutations has yet to be fully elucidated and further study is warranted. Clinical correlation is recommended.

Last updated: 2019-08-29 17:55:49 UTC
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PMKB Bot
  • Genes
  • Variants
  • Interpretations
  • Tumor Types
  • Primary Sites
  • Activity

Disclaimer: You assume full responsibility for all risks associated with using this PMKB website. The Englander Institute for Precision Medicine at Weill Cornell Medicine makes no guarantee of the comprehensiveness, reliability or accuracy of the information on this website and assumes no responsibility for errors in the information associated with this web site. Healthcare providers and patients must integrate all clinical and laboratory findings as well as information from a variety of sources before deciding on appropriate clinical care options.


When using PMKB, please cite: Huang et al., JAMIA 2017


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