Population-based estimates of age-specific cumulative risk of breast cancer for pathogenic variants in ATM

Abstract

Background Multigene panel tests for breast cancer predisposition routinely include ATM as it is now a well-established breast cancer predisposition gene. Methods We included ATM in a multigene panel test applied to the Australian Breast Cancer Family Registry (ABCFR), a population-based case–control–family study of breast cancer, with the purpose of estimating the prevalence and penetrance of heterozygous ATM pathogenic variants from the family data, using segregation analysis. Results The estimated breast cancer hazard ratio for carriers of pathogenic ATM variants in the ABCFR was 1.32 (95% confidence interval 0.45–3.87; P = 0.6). The estimated cumulative risk of breast cancer to age 80 years for heterozygous ATM pathogenic variant carriers was estimated to be 13% (95% CI 4.6–30). Conclusions Although ATM has been definitively identified as a breast cancer predisposition gene, further evidence, such as variant-specific penetrance estimates, are needed to inform risk management strategies for carriers of pathogenic variants to increase the clinical utility of population testing of this gene.

ATM c.7570G>C is a high‐risk allele for breast cancer

“…ATM gene is an established breast cancer susceptibility gene, generally placed in the moderate‐risk category with a combined estimation of 2‐fold risk for the predisposing alleles. The estimated lifetime breast cancer risk varies in different studies from 13% to 33% by the age of 80 years 15,23‐25 . According to the ClinVar database, up to 1500 PVs have been reported in the ATM gene in the context of A‐T syndrome and/or hereditary cancer‐predisposing syndrome.…”

“…The estimated lifetime breast cancer risk varies in different studies from 13% to 33% by the age of 80 years. 15 , 23 , 24 , 25 According to the ClinVar database, up to 1500 PVs have been reported in the ATM gene in the context of A‐T syndrome and/or hereditary cancer‐predisposing syndrome. Previous studies have suggested that the breast cancer risk is higher for carriers of an ATM loss‐of‐function variants than it is for carriers of an ATM deleterious missense variants (MVs).…”

Surgical options for patients with early-stage breast cancer and pathogenic germline variants: an oncologist perspectives

“…Heterozygous pathogenic variant in ATM is associated with a 13-33% cumulative lifetime risk for breast cancer ( 83 , 84 ). Risk-reducing mastectomy is not recommended for carriers; however, it might be considered based on personal and family history.…”