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ATM
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Interpretation 2314
Tier 3
ATM
Variants
ATM F858L
Primary Sites
Ampulla (Pancreaticobiliary Duct)
Tumor Types
Adenocarcinoma
Interpretation

ATM is a member of the protein superfamily of phosphatidylinositol 3-kinase related serine/threonine kinases (PIKKs). ATM is part of many signaling networks, including cell metabolism and growth, oxidative stress, and chromatin remodeling, all of which can affect cancer progression. Although ATM is considered to be a tumor suppressor, ATM signaling may be advantageous to cancer cells in some settings, particularly in resistance to radio- and chemotherapeutic treatment. Germline ATM mutations are the defining feature of ataxia telangiectasia syndrome, a rare, neurodegenerative, autosomal disorder. ATM somatic mutations are associated with endometrial, colon, pancreatic, breast cancers and urothelial cancers. ATM-mutant cancers are increasingly sensitive to DNA damaging agents due to deficits in DNA repair pathways, and ATM loss may result in better response to checkpoint inhibition in some cancers. For this reason, the use of ATM inhibitors in cancer therapy is under exploration. Genetic alterations of ATM have been identified in 5% of pancreatic adenocarcinomas. ATM F858L has been identified in the scientific literature, but has not been biochemically characterized and therefore, its effect on ATM protein function is unknown. According to ClinVar, this variant is considered to be a benign/likely benign germline variant (https://preview.ncbi.nlm.nih.gov/clinvar/variation/132736/). Clinical correlation is recommended.

Citations
  1. Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007 May 25;316(5828):1160-6.
  2. Choi M, Kipps T, Kurzrock R. ATM Mutations in Cancer: Therapeutic Implications. Mol Cancer Ther. 2016 Aug;15(8):1781-91. doi:
  3. 10.1158/1535-7163.MCT-15-0945. Epub 2016 Jul 13. Review. PubMed PMID: 27413114.
  4. Fletcher et al. Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls. Cancer Epidemiol Biomarkers Prev. 2010; 19(9): 2143-2151.
  5. Mangone et al. ATM gene mutations in sporadic breast cancer patients from Brazil. SpringerPlus DOI 10.1186/s40064-015-0787-z.
  6. Cremona et al. ATM signalling and cancer. Oncogene. 2014; 33:3351-3360.
  7. Anika Maria Weber et al. ATM and ATR as therapeutic targets in cancer. Pharmacology & Therapeutics. 2015; 129:124-138.
  8. Comprehensive TCGA PanCanAtlas (https://gdc.cancer.gov/about-data/publications/pancanatlas).
  9. Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, North B, Jayatilake H, Barfoot R, Spanova K, McGuffog L, Evans DG, Eccles D; Breast Cancer Susceptibility Collaboration (UK), Easton DF, Stratton MR, Rahman N. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006 Aug;38(8):873-5.
  10. Jain R, Savage MJ, Forman AD, Mukherji R, Hall MJ. The Relevance of Hereditary Cancer Risks to Precision Oncology: What Should Providers Consider When Conducting Tumor Genomic Profiling? J Natl Compr Canc Netw. 2016 Jun;14(6):795-806.
  11. ClinVar. https://preview.ncbi.nlm.nih.gov/clinvar/variation/132736/
Last updated: 2019-01-22 18:44:03 UTC
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