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551 Background: Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein truncating variant CHEK2c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. Methods: We conducted a genetic screen of CHEK2 in an Australian population-based case-control-family study of breast cancer. This study is focused on disease at an early age and participants were unselected for family history. The age-specific cumulative risk (penetrance) of breast cancer was estimated using segregation analysis. Results: The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5-9.5; p < 0.0001) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02-11.6) and the HR for carriers of all other CHEK2 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. Conclusions: These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.

Simple Summary It is well established that women who carry pathogenic CHEK2 variants have about a 3-fold increased risk of developing breast cancer. CHEK2 is now commonly included in genetic tests for breast cancer predisposition and increasingly used to inform the clinical management of women who are identified to carry pathogenic variants. Important information for counselling these women includes knowing how breast cancer risk, due to having a pathogenic variant in CHEK2, changes over a woman’s lifetime. This information is currently not well established. By conducting a population-based case-control-family study of pathogenic CHEK2 variants we aimed to provide this information and estimated the penetrance (age-specific cumulative risk) of breast cancer to be 18% (95% CI 11–30%) to age 60 years and 33% (95% CI 21–48%) to age 80 years. These findings provide new and important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2. Abstract Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant CHEK2 c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic CHEK2 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 CHEK2 variants (combined) was 4.9 (95% CI 2.5–9.5) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02–11.6) and the HR for carriers of all other CHEK2 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 CHEK2.