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%).

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.

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.

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.

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.

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.

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.

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

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

This gene is a known cancer gene. ARID1A/BAF250A subunit of the SWI/SNF (BAF) chromatin remodeling complex has emerged as recurrently mutated in a broad array of tumor types and a potential tumor suppressor. There is evidence indicating that ARID1A-mutated cancers may be subjected to therapeutic intervention.

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.

BCL2 genomic Amplification may be associated with sensitivity to BCL2 inhibitors, however these inhibitors are currently undergoing clinical trials and their efficacy and/or lack of toxicity has not yet been demonstrated.

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).