Apparent regional differences in the spectrum of BARD1 pathogenic variants in Spanish population and importance of copy number variants

Abstract

Only up to 25% of the cases in which there is a familial aggregation of breast and/or ovarian cancer are explained by germline mutations in the well-known BRCA1 and BRCA2 high-risk genes. Recently, the BRCA1-associated ring domain (BARD1), that partners BRCA1 in DNA repair, has been confirmed as a moderate-risk breast cancer susceptibility gene. Taking advantage of next-generation sequencing techniques, and with the purpose of defining the whole spectrum of possible pathogenic variants (PVs) in this gene, here we have performed a comprehensive mutational analysis of BARD1 in a cohort of 1946 Spanish patients who fulfilled criteria to be tested for germline pathogenic mutations in BRCA1 and BRCA2. We identified 22 different rare germline variants, being 5 of them clearly pathogenic or likely pathogenic large deletions, which account for 0.26% of the patients tested. Our results show that the prevalence and spectrum of mutations in the BARD1 gene might vary between different regions of Spain and expose the relevance to test for copy number variations.

Germline heterozygous exons 8–11 pathogenic BARD1 gene deletion reported for the first time in a family with suspicion of a hereditary colorectal cancer syndrome: more than an incidental finding?

“…A more recently published study in families with breast-ovarian cancer aggregation revealed the presence of five different large deletions in the BARD1 gene in five breast cancer patients. In two of the cases, there was a confirmed history of CRC among their relatives, but no data on cosegregation were provided [ 30 ].…”

A Large Case-Control Study Performed in Spanish Population Suggests That RECQL5 Is the Only RECQ Helicase Involved in Breast Cancer Susceptibility

“…A total of 1993 index cases from BRCAX families were included that had previously tested negative for pathogenic or likely pathogenic variants in the BRCA1, BRCA2, PALB2, ATM, CHEK2, BRIP1, RAD51C, and RAD51D genes, either with the NGS gene panel used here or with that described in Benito-Sánchez et al, 2022 [32]. Samples came from seven Spanish centers: Spanish National Cancer Center (CNIO) (Madrid, Spain), Hospital Clínico San Carlos (Madrid, Spain), Hospital General La Mancha Centro (Ciudad Real, Spain), Complejo Hospitalario Universitario de Albacete, Hospital General Universitario de Ciudad Real, Hospital Virgen de la Luz (Cuenca, Spain), and Laboratorio de Cáncer Hereditario of Instituto de Biología y Genética Molecular (Universidad de Valladolid, Valladolid, Spain).…”