Case Review: Whole-Exome Sequencing Analyses Identify Carriers of a Known Likely Pathogenic Intronic BRCA1 Variant in Ovarian Cancer Cases Clinically Negative for Pathogenic BRCA1 and BRCA2 Variants.

Autor:	Alenezi WM; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.; Cancer Research Program, Centre for Translational Biology, The Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada.; Department of Medical Laboratory Technology, Taibah University, Medina 42353, Saudi Arabia., Fierheller CT; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.; Cancer Research Program, Centre for Translational Biology, The Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Revil T; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.; McGill Genome Centre, McGill University, Montreal, QC H3A 0G1, Canada., Serruya C; Cancer Research Program, Centre for Translational Biology, The Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Mes-Masson AM; Département de Médecine, Université de Montréal, Montreal, QC H3T 1J4, Canada.; Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC H2X 0A9, Canada., Foulkes WD; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.; Cancer Research Program, Centre for Translational Biology, The Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada.; Lady Davis Institute for Medical Research of the Jewish General Hospital, Montreal, QC H3T 1E2, Canada.; Department of Medical Genetics, McGill University Health Centre, Montreal, QC H3H 1P3, Canada.; Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada.; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 1G5, Canada., Provencher D; Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC H2X 0A9, Canada.; Division of Gynecologic Oncology, Université de Montréal, Montreal, QC H4A 3J1, Canada., El Haffaf Z; Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC H2X 0A9, Canada.; Service de Médecine Génique, Centre Hospitalier de l'Université de Montréal, Montreal, QC H2X 0A9, Canada., Ragoussis J; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.; McGill Genome Centre, McGill University, Montreal, QC H3A 0G1, Canada., Tonin PN; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.; Cancer Research Program, Centre for Translational Biology, The Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada.; Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
Jazyk:	angličtina
Zdroj:	Genes [Genes (Basel)] 2022 Apr 15; Vol. 13 (4). Date of Electronic Publication: 2022 Apr 15.
DOI:	10.3390/genes13040697
Abstrakt:	Background: Detecting pathogenic intronic variants resulting in aberrant splicing remains a challenge in routine genetic testing. We describe germline whole-exome sequencing (WES) analyses and apply in silico predictive tools of familial ovarian cancer (OC) cases reported clinically negative for pathogenic BRCA1 and BRCA2 variants. Methods: WES data from 27 familial OC cases reported clinically negative for pathogenic BRCA1 and BRCA2 variants and 53 sporadic early-onset OC cases were analyzed for pathogenic variants in BRCA1 or BRCA2. WES data from carriers of pathogenic BRCA1 or BRCA2 variants were analyzed for pathogenic variants in 10 other OC predisposing genes. Loss of heterozygosity analysis was performed on tumor DNA from variant carriers. Results: BRCA1 c.5407-25T>A intronic variant, identified in two affected sisters and one sporadic OC case, is predicted to create a new splice effecting transcription of BRCA1. WES data from BRCA1 c.5407-25T>A carriers showed no evidence of pathogenic variants in other OC predisposing genes. Sequencing the tumor DNA from the variant carrier showed complete loss of the wild-type allele. Conclusions: The findings support BRCA1 c.5407-25T>A as a likely pathogenic variant and highlight the importance of investigating intronic sequences as causal variants in OC families where the involvement of BRCA1 is highly suggestive.
Databáze:	MEDLINE
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