Summary of BARD1 Mutations and Precise Estimation of Breast and Ovarian Cancer Risks Associated with the Mutations

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.

Keywords: BARD1; breast cancer; cancer risk; meta-analysis; mutation; ovarian cancer; pathogenic variant.

Figure 1

Maps of deleterious PVs in BARD1. PVs are shown alongside the BARD1 coding sequence with the indicated exon structure and the protein functional domains. The size of a PV symbol (circle) is proportional to the number of PVs, and color indicates the type of PV. (A) PVs detected in BC (above) and OC (below) cases. (B) PVs reported in noncancer gnomAD controls. The total number of detected PVs and the total number of cases and controls tested for the variants are indicated in parentheses; note that the total number of tested subjects differs substantially between groups.

Figure 2

Summary of the BC and OC risk (OR) associated with BARD1 PVs. (A) The graph showing gene-specific and variant-specific ORs. The gene-specific OR is provided for all ethnicities combined and separately for European and Asian populations. “Only NGS studies” and “Without DC studies” demonstrate the results of repeated association analyses without studies applying older technologies and without studies publishing results of multigene testing in samples submitted to diagnostic companies, respectively. Diamonds and horizontal lines indicate the OR values and 95% CIs, respectively. Black and blue symbols represent BC and OC, respectively. Green, orange, and red vertical lines highlight an OR of 1 (no risk), an OR of 2 (the threshold for moderate risk), and an OR of 4 (the threshold for high risk), respectively. * or ** next to the OR symbol indicates a p-value < 0.05 or < 0.01, respectively. (B) The table showing the exact numbers and percentages (in the bracket) of detected PVs in either BC (black fonts) or OC (blue fonts) cases and in controls, as well as ORs with 95% CIs and p-values (the values correspond to the particular OR symbols shown in the graph on the left).