Characterization of a Genetic Variant in BARD1 in Subjects Undergoing Germline Testing for Hereditary Tumors

Hereditary breast and ovarian cancer (HBOC) syndrome accounts for 5-10% of all breast and ovarian cancers, with <i>BRCA1</i> and <i>BRCA2</i> pathogenic variants being the most common genetic alterations. However, additional genes such as <i>BARD1</i>, whose protein product interacts with BRCA1 via its N-terminal RING domain, have been implicated as low-penetrance contributors to cancer risk. This study aimed to investigate the frequency and distribution of the <i>BARD1</i> variant c.1518_1519delinsCA (p.Val507Met) in a cohort of 920 patients undergoing genetic testing for hereditary cancer predisposition. Next Generation Sequencing (NGS) was performed using a 28-gene panel, and allelic frequencies of <i>BARD1</i> were analyzed. Among 920 patients, 159 (17.28%) were pure heterozygous for the c.1518_1519delinsCA variant. Notably, c.1519G>A was never observed without c.1518T>C, suggesting a strong linkage between the two variants. The allele frequencies observed (34.51% for A at c.1519 and 77.88% for C at c.1518) challenge current reference genome expectations. Data from the ALFA database confirmed that these frequencies are consistent with population-level variation, not sample bias. Our findings raise the hypothesis that the reference allele at position c.1518 may not reflect the true wild-type sequence. While both c.1518T>C and c.1519G>A are individually classified as benign, their combined occurrence as a dinucleotide substitution (c.1518_1519delinsCA) warrants further investigation. These results underscore the importance of accurate variant annotation and population-specific frequency data for clinical interpretation of NGS findings. Although <i>BARD1</i> remains a low-frequency contributor to HBOC compared to <i>BRCA1/2</i>, its inclusion in multigene panels is supported by the potential relevance of such complex variants.