Germline pathogenic variants in the Ataxia Telangiectasia Mutated (ATM) gene are associated with high and moderate risks for multiple cancers. Cancer prevention research (Philadelphia, Pa.) Hall, M. J., Bernhisel, R. n., Hughes, E. n., Larson, K. n., Rosenthal, E. T., Singh, N. A., Lancaster, J. M., Kurian, A. W. 2021


Pathogenic variants (PVs) in ATM are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate ATM PV cancer risks independent of family cancer history. This analysis included patients referred for hereditary cancer testing with a multi-gene panel (N=627,742). Cancer risks for ATM PV carriers (N=4,607) were adjusted for family history using multivariable logistic regression and reported as odds ratios (ORs) with 95% confidence intervals (CIs). Sub-analyses of the c.7271T>G missense PV were conducted. Moderate-to-high risks for pancreatic (OR 4.21; 95% CI 3.24-5.47), prostate (OR 2.58; 95% CI 1.93-3.44), gastric (OR 2.97; 95% CI 1.66-5.31) and invasive ductal breast (OR 2.03; 95% CI 1.89-2.19) cancers were estimated for ATM PV carriers. Notably, c.7271T>G was associated with higher invasive ductal breast cancer risk (OR 3.76, 95% CI 2.76-5.12) than other missense and truncating ATM PVs. Low-to-moderate risks were seen for ductal carcinoma in situ (OR 1.80, 95% CI 1.61-2.02), male breast cancer (OR 1.72, 95% CI 1.08-2.75), ovarian cancer (OR 1.57; 95% CI 1.35-1.83), colorectal cancer (OR 1.49; 95% CI 1.24-1.79) and melanoma (OR 1.46; 95% CI 1.18-1.81). ATM PVs are associated with multiple cancer risks and, while professional society guidelines support that carriers are eligible for increased breast and pancreatic cancer screening, increased screening for prostate and gastric cancer may also be warranted. c.7271T>G is associated with high risk for breast cancer, with a three to four-fold risk increase that supports consideration of strategies for prevention and/or early detection.

View details for DOI 10.1158/1940-6207.CAPR-20-0448

View details for PubMedID 33509806