Abstract
Previous studies have suggested the missense variant NM_000051.4(ATM):c.7271T>G is associated with a high risk of breast cancer (BC), but the magnitude of the association, and the associations with other cancer types, are unclear. Cancer associations were evaluated using sequence data linked to cancer registration data (348 488 participants, 56 640 cancer cases) from UK Biobank (UKB), and targeted sequence or genome-wide array data (126 428 cases, 115 495 controls) from the Breast Cancer Association Consortium (BCAC). The magnitudes of the association of c.7271T>G with invasive BC were similar using UKB (relative risk (RR): 4.57, 95% CI: 2.25 to 9.30, p=2.7×10-5) and BCAC (OR: 4.11, 2.05 to 8.26, p=6.9×10-5). In UKB, c.7271T>G was associated with increased risks of prostate cancer (4.84, 2.27 to 10.33, p=4.54×10-5), and any other cancer (males 2.79, 1.33 to 5.85, p=0.0066; females 3.15, 1.49 to 6.63, p=0.0026). Estimated cumulative risks of all cancers to age 80 years were 87% in males (prostate cancer 43%) and 84% in females (BC 43%). The estimated RRs are consistent with c.7271T>G being associated with a risk of more than twice that for Ataxia-Telangiectasia Mutated protein-truncating variants, for all cancers. These data justify specific management of c.7271T>G carriers.