The Genetic and Molecular Analyses of Rare Candidate Germline BRIP1/FANCJ Variants Implicated in Hereditary Breast and Ovarian Cancers
Year: 2026
Type: article
Study design: Observational Study
Abstract: Five rare variants in BRIP1/FANCJ, initially identified in ovarian cancer (OC) or breast cancer (BC) cases by the adult hereditary cancer clinics, were investigated for their candidacy as clinically relevant variants. These variants were investigated genetically in a population exhibiting genetic drift and molecularly assayed for biological impact. Using in silico tools, population-based genetic databases and other resources, three of the five reported BRIP1 variants were likely to be damaging: c.797C>T; p.Thr266Met, c.2087C>T; p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61. The carrier frequencies ranged from 0 to 0.7% in ancestry-defined cancer groups comprising 47 OC families, 49 hereditary breast and ovarian cancer syndrome families, 142 hereditary breast cancer syndrome families, 435 sporadic OC cases and 563 sporadic BC cases and 0–0.2% in 1025 population-matched controls. Multiple carriers of the these variants were identified in additional population-matched cancer cases. Of the five reported BRIP1 variants, p.Thr266Met, p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61, which were predicted to be damaging, conferred cellular sensitivity to mitomycin C and cisplatin unlike p.Ser139Ala and p.Ala406Ser. Collectively, our investigation implicates BRIP1 c.797C>T; p.Thr266Met, c.2087C>T; p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61 as deleterious variants in OC and BC.
DOI: 10.3390/ijms27021037
Authors: Wejdan M. Alenezi, Larissa Milano, Caitlin T. Fierheller, Corinne Serruya, Timothée Revil, Kathleen K. Oros, Jeffrey P. Bruce, Dan Spiegelman, Trevor Pugh, Anne-Marie Mes-Masson, Diane Provencher, William D. Foulkes, Zaki El Haffaf, Guy Rouleau, Luigi Bouchard, Celia M. T. Greenwood, Jiannis Ragoussis, Jean-Yves Masson, Patricia N. Tonin
Institutions: McGill University Health Centre, Research Institute of the McGill University Health Centre, McGill University, Centre hospitalier universitaire de Québec, Hôpital de l'Enfant-Jésus, Université Laval, McGill Genome Centre, Jewish General Hospital, Lady Davis Institute for Medical Research, University Health Network, Princess Margaret Cancer Centre, Montreal Neurological Institute and Hospital, Ontario Institute for Cancer Research, University of Toronto, Centre Hospitalier de l’Université de Montréal, Institut du cancer de Montréal, Université de Montréal, Université de Sherbrooke, Centre Hospitalier Universitaire de Sherbrooke, Centre Intégré Universitaire de Santé et de Services Sociaux du Saguenay–Lac-Saint-Jean, Hôpital de Chicoutimi
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,499
OpenAlex ID: W7125021847