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

TL;DR

This study examines a genetic variant in BARD1 among patients tested for hereditary cancer, finding it occurs more frequently than expected and challenges current reference genome assumptions.

Contribution

The study identifies a novel dinucleotide substitution in BARD1 and highlights its potential clinical relevance despite being classified as benign.

Findings

17.28% of patients were heterozygous for the BARD1 c.1518_1519delinsCA variant.

Strong linkage was observed between c.1518T>C and c.1519G>A, suggesting a dinucleotide substitution.

Allele frequencies at c.1518 and c.1519 challenge current reference genome expectations.

Abstract

Hereditary breast and ovarian cancer (HBOC) syndrome accounts for 5–10% of all breast and ovarian cancers, with BRCA1 and BRCA2 pathogenic variants being the most common genetic alterations. However, additional genes such as BARD1, 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 BARD1 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 BARD1 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 BARD1 remains a low-frequency contributor to HBOC compared to BRCA1/2, its inclusion in multigene panels is supported by the potential relevance of such complex variants.

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