Genetic and molecular analyses of candidate germline BRIP1/FANCJ variants implicated in breast and ovarian cancer

Five rare variants in BRIP1/FANCJ , initially reported in ovarian (OC) or breast (BC) cancer 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 0-0.7% in ancestry defined cancer groups comprised of 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 same variants were identified in additional population-matched cancer cases. Of the five reported BRIP1 variants, p.Thr266Met, p.Pro696Leu and 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 p.Thr997ArgfsTer61 as deleterious variants in OC and BC. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The work was supported in part by the Department of Medicine, McGill University to P.N.T.; Saudi Arabian Cultural Bureau to P.N.T. and W.M.A.; The Canadian Institute for Health Research (CIHR) operating grants (PCC-156736 to P.N.T., C.M.T.G. and J.R.) and (PJT-156124 to P.N.T. and J.R.); Cancer Research Society and Ovarian Cancer Canada partnership grant (21123 to P.N.T.); Department of Medicine, McGill University Grant to P.N.T.; the Fond de la recherche du Quebec en Sante (FRQS) and Quebec Breast Cancer Foundation network grants to P.N.T.; Compute Canada resource allocation project wst-164 and Genome Canada Genome Technology Platform award to J.R.; CIHR foundation grant to J.Y.M (DN-388879); Gen3G has been supported over the time by FRQS grant (20697 to M.F.H.); CIHR grant (MOP-115071 to M.F.H.) and (PJT-152989 to L.B.); American Diabetes Association (ADA) accelerator award (1-15-ACE-26 to M.F.H.). LB is a senior research scholar from FRQS. The sequencing of the Gen3G offspring has been sponsored by Fonds de recherche du Quebec, McGill University and Universite de Sherbrooke. Ovarian tumour banking was supported by the Banque de tissus et de donnees of the Reseau de recherche sur le cancer of the FRQS affiliated with the Canadian Tumour Repository Network (CTRNet). The RI-MUHC and CRCHUM receive support from the FRQS. J.-Y.M. is a Tier I Canada Research Chair in DNA repair and cancer therapeutics. W.M.A. was supported by Taibah University Scholarship Award and C.T.F. was supported in part by RI-MUHC Scholarship Award and James O and Maria Meadows Award. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This project was conducted with approval and in accordance with the guidelines of The McGill University Health Centre Research Ethics Board (MP-37-2019-4783). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors