Pathogenic Variants in BRIP1, RAD51C, and RAD51D Identified with Multi-Gene Panel Testing for Hereditary Cancers

Background: Professional society guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) for women with pathogenic variants (PVs) in ovarian cancer-risk genes. Personalization of that intervention is based on gene-specific phenotypes; however, the age of ovarian cancer diagnosis in women with PVs in moderate penetrance ovarian cancer-risk genes is not well characterized. Women who had hereditary cancer panel testing from September 2013-May 2019 were included (N=631,950). Clinical/demographic information was compared for women with a PV in BRIP1, RAD51C, or RAD51D versus in BRCA1 or BRCA2. Results: : PVs in BRIP1, RAD51C, or RAD51D were identified in 0.5% of all tested women but in 1.6% of women with a history of ovarian cancer (~3-fold increase). PVs in BRCA1 or BRCA2 were identified in 2.4% of all tested women but in 6.1% of women with a history of ovarian cancer (~2.5-fold increase). The proportion of women with a personal or family history of ovarian cancer was similar among women with a PV in BRIP1 , RAD51C , RAD51D , BRCA1 , or BRCA2 . The median age at ovarian cancer diagnosis was 53 years in BRCA1 , 59 years for BRCA2 , 65 years for BRIP1 , 62 years for RAD51C , and 57 years for RAD51D . Conclusions: : These data reinforce the importance of identifying PVs in moderate penetrance ovarian cancer-risk genes. The age at ovarian cancer diagnosis was older for women with PVs in BRIP1, RAD51C, or RAD51D , suggesting that it is safe to delay RRSO until age 45-50 in RAD51D PV carriers and possibly, until age 50-55 in BRIP and RAD51C PV carriers.