Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in CHEK2 : Findings from the Australian Breast Cancer Family Registry

Case-control studies of breast cancer have consistently shown that pathogenic variants in are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic variants (combined) was 4.9 (95% CI 2.5-9.5) relative to non-carriers. The HR for carriers of the c.1100delC variant was estimated to be 3.5 (95% CI 1.02-11.6) and the HR for carriers of all other variants combined was estimated to be 5.7 (95% CI 2.5-12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11-30%) and 33% (95% CI 21-48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in .