Management of individuals with heterozygous germline pathogenic variants in ATM: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Purpose: ATM germline pathogenic variants (GPVs) are associated with a moderately increased risk of female breast cancer, pancreatic cancer, and prostate cancer. Resources for managing ATM heterozygotes in clinical practice are limited. Methods: An international workgroup developed a clinical practice resource to guide management of ATM heterozygotes using peer-reviewed publications and expert opinion. Results: Although ATM is a moderate (intermediate) penetrance gene, cancer risks may be considered as a continuous variable, influenced by family history and other modifiers. ATM GPV heterozygotes should generally be offered enhanced breast surveillance according to their personalized risk estimate and country-specific guidelines and, generally, risk-reducing mastectomy is not recommended. Prostate cancer surveillance should be considered. Pancreatic cancer surveillance should be considered based on assessment of family history, ideally as part of a clinical trial, with existence of country-specific guidelines. For ATM GPV heterozygotes who develop cancer, radiation therapy decisions should not be influenced by the genetic result. Although poly-adenosine diphosphate ribose polymerase inhibitors are licensed for use in metastatic castration-resistant prostate cancer and ATM GPVs, the evidence-base is currently weak. Conclusion: Systematic prospective data collection is needed to establish the spectrum of ATM-associated cancer and determine the outlines of surveillance, response to cancer treatment, and survival.