Functional analysis of clinical BARD1 germline variants

• DOI: 10.1101/mcs.a004093
• Publication Date: 2019-08-01T18:45:16Z
• Authors: Ming Ren Toh; Siao Ting Chong; Sock Hoai Chan; Chen Ee Low; Nur Diana Binte I...; Jing Quan Lim; Eliza Courtney; Joanne Ngeow
• Keywords: Adult; Male; Ovarian Neoplasms; 0301 basic medicine; DNA Repair; BRCA1 Protein; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; Breast Neoplasms; Triple Negative Breast Neoplasms; BARD1 Gene; Middle Aged; Germline Mutation; 3. Good health; 03 medical and health sciences; Germ Cells; Protein Domains; Humans; :Medicine [Science]; Female; Colorectal Neoplasms; Germ-Line Mutation; Research Article

Germline pathogenic variants in BRCA1/2 account for one-third of familial breast cancers. The majority BRCA1 function requires heterodimerization with BARD1. In contrast to , BARD1 is a low-penetrance gene an unclear clinical relevance, partly because limited functional evidence. Using patient-derived lymphoblastoid cells, we functionally characterized two (c.1833dupT, c.2099delG) and three uncertain significance (VUSs) (c.73G>C, c.1217G>A, c.1918C>A). Three these patients had cancers, whereas the remaining colorectal cancers ( n = 3). Both developed aggressive disease phenotypes such as triple-negative cancer high grades. As encompasses multiple domains, including those apoptosis homologous recombination repair, hypothesized that being impaired would correspond domain where variant was located. Variants c.1918C>A, c.1833dupT, c.2099delG, located within proximal apoptotic domains ankyrin BRCT, were associated apoptosis. Conversely, preserved c.73G>C, which distant from domain. All displayed normal RAD51 colocalization, consistent their location distal BRCA1—and RAD51-binding domains. view deficient apoptosis, VUSs (c.1217G>A c.1918C>A) may be or likely variants. summary, analysis combination assays and, more importantly, use appropriate consideration variant's location.