Abstract
Over the last two decades, numerous BARD1 mutations/pathogenic variants (PVs) have been found in patients with breast cancer (BC) and ovarian cancer (OC). However, their role in BC and OC susceptibility remains controversial, and strong evidence-based guidelines for carriers are not yet available. Herein, we present a comprehensive catalog of BARD1 PVs identified in large cumulative cohorts of ~48,700 BC and ~20,800 OC cases (retrieved from 123 studies examining the whole coding sequence of BARD1). Using these resources, we compared the frequency of BARD1 PVs in the cases and ~134,100 controls from the gnomAD database and estimated the effect of the BARD1 PVs on BC and OC risks. The analysis revealed that BARD1 is a BC moderate-risk gene (odds ratio (OR) = 2.90, 95% CIs:2.25-3.75, p < 0.0001) but not an OC risk gene (OR = 1.36, 95% CIs:0.87-2.11, p = 0.1733). In addition, the BARD1 mutational spectrum outlined in this study allowed us to determine recurrent PVs and evaluate the variant-specific risk for the most frequent PVs. In conclusion, these precise estimates improve the understanding of the role of BARD1 PVs in BC and OC predisposition and support the need for BARD1 diagnostic testing in BC patients.