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

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 ( and . BRCA1-associated ring domain 1 (), nuclear partner of , 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 truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive 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 truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating variants with overall risk (odds ratio (OR) = 3.78; CI = 2.10-6.48; = 1.16 × 10). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18; CI = 2.10-7.70; = 5.45 × 10). Furthermore, deleterious variants were enriched among triple-negative BC patients (OR = 5.40; CI = 1.77-18.15; = 0.001) compared to other BC subtypes. Our results support the role of as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors.