BARD1 Pathogenic Variants Are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort

Abstract

Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (<i>BRCA1</i> and <i>BRCA2)</i>. BRCA1-associated ring domain 1 (<i>BARD1</i>), nuclear partner of <i>BRCA1</i>, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of <i>BARD1</i> truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive <i>BARD1</i> screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous <i>BARD1</i> truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating <i>BARD1</i> variants with overall risk (odds ratio (OR) = 3.78; CI = 2.10-6.48; <i>p</i> = 1.16 × 10^-5). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18; CI = 2.10-7.70; <i>p</i> = 5.45 × 10^-5). Furthermore, deleterious <i>BARD1</i> variants were enriched among triple-negative BC patients (OR = 5.40; CI = 1.77-18.15; <i>p</i> = 0.001) compared to other BC subtypes. Our results support the role of <i>BARD1</i> as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors.