Rare BRIP1 missense alleles confer risk for ovarian and breast cancer.
Germline loss-of-function mutations in BRIP1 are associated with ovarian carcinoma and may also contribute to breast cancer risk, particularly among patients who develop disease at an early age. Normal BRIP1 activity is required for DNA interstrand crosslink repair, and is thus central to the maintenance of genome stability. Although pathogenic mutations have been identified in BRIP1, genetic testing more often reveals missense variants for which the impact on molecular function and subsequent roles in cancer risk are uncertain. Next generation sequencing of germline DNA in 2,160 early-onset breast cancer and 1,199 ovarian cancer patients revealed nearly 2% of patients carry a very rare missense variant (MAF<0.0001) in BRIP1. This is 3 fold higher than the frequency of all rare BRIP1 missense alleles reported in more than 60,000 individuals of the general population (p<0.0001, Chi-square). Using CRISPR-Cas9 gene editing technology and rescue assays, we functionally characterized 20 of these missense variants, focusing on the altered protein's ability to repair interstrand crosslink damage. 75% of the characterized variants rendered the protein hypomorph or null. In a clinical cohort of >117,000 breast and ovarian cancer patients who underwent panel testing, the combined odds ratio associated with BRIP1 hypomorph or null missense carriers compared to the general population was 2.30 (95%CI=1.60-3.30, p<0.0001). These findings suggest that novel missense variants within the helicase domain of BRIP1 may confer risk for both breast and ovarian cancer and highlight the importance of functional testing for additional variants.