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402554 | New Interpretation | 01/22/2019 1:25 PM |
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The interpretation was not yet created, or had been deleted.After (Current Version)
Tier 3InterpretationATM is a member of the protein superfamily of phosphatidylinositol 3-kinase related serine/threonine kinases (PIKKs). ATM functions as a tumor suppressor that initiates DNA damage checkpoint signaling. Germline loss-of-function mutations in ATM have been identified in the autosomal recessive disorder Ataxia telangiectasia. Somatic mutations in ATM have been identified in lymphoid malignancies and a selection of solid tumors. 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. Genetic alterations of ATM have been identified in approximately 10% of lung adenocarcinomas. One study predicted impaired ATM kinase activity in the setting of ATM R2691C mutation based on structural modeling; however, these results have not been validated biochemically. Of note, this variant is reported in ClinVar as a germline variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/133636/). Correlation with other clinical and lab findings is recommended.
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Citations- Guarini A, Marinelli M, Tavolaro S, Bellacchio E, Magliozzi M, Chiaretti S, De Propris MS, Peragine N, Santangelo S, Paoloni F, Nanni M, Del Giudice I, Mauro FR, Torrente I, Foa R. ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression. Haematologica. 2012 Jan;97(1):47-55.
- Zhang T, Penicud K, Bruhn C, Loizou JI, Kanu N, Wang ZQ, Behrens A.
- Competition between NBS1 and ATMIN controls ATM signaling pathway choice. Cell Rep. 2012 Dec 27;2(6):1498-504.
- Reiman A, Srinivasan V, Barone G, Last JI, Wootton LL, Davies EG, Verhagen MM, Willemsen MA, Weemaes CM, Byrd PJ, Izatt L, Easton DF, Thompson DJ, Taylor AM. Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours. Br J Cancer. 2011 Aug 9;105(4):586-91.
- Choi M, Kipps T, Kurzrock R. ATM Mutations in Cancer: Therapeutic
- Implications. Mol Cancer Ther. 2016 Aug;15(8):1781-91.
- Teo MY, Seier K, Ostrovnaya I, Regazzi AM, Kania BE, Moran MM, Cipolla CK, Bluth MJ, Chaim J, Al-Ahmadie H, Snyder A, Carlo MI, Solit DB, Berger MF, Funt S,Wolchok JD, Iyer G, Bajorin DF, Callahan MK, Rosenberg JE. Alterations in DNA Damage Response and Repair Genes as Potential Marker of Clinical Benefit From PD-1/PD-L1 Blockade in Advanced Urothelial Cancers. J Clin Oncol. 2018 Jun 10;36(17):1685-1694.
- Comprehensive TCGA PanCanAtlas (https://gdc.cancer.gov/about-data/publications/pancanatlas)
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Last updated: 2019-01-22 18:25:58 UTC
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