title: Identification of six pathogenic RAD51C mutations via mutational screening of 1228 Danish individuals with increased risk of hereditary breast and/or ovarian cancer.
abstract: Germ-line mutations in the RAD51C gene have recently been identified in families with breast and ovarian cancer and have been associated with an increased risk of ovarian cancer. In this study, we describe the frequency of pathogenic RAD51C mutations identified in Danish breast and/or ovarian cancer families. We screened the RAD51C gene in 1228 Danish hereditary breast and/or ovarian cancer families by next-generation sequencing analysis. The frequency of the identified variants was examined in the exome sequencing project database and in data from 2000 Danish exomes and the presumed significance of missense and intronic variants was predicted by in silico analysis. We identified six families with a pathogenic mutation in RAD51C, including three frameshift mutations, one nonsense mutation, and 2 missense mutations. Overall, pathogenic RAD51C mutations were identified in 0.5 % of Danish families with increased risk of hereditary breast and/or ovarian cancer. Moreover, we identified 24 additional RAD51C variants of which 14 have not been previously reported in the literature. In this study, we determine the prevalence of RAD51C mutations in Danish breast and/or ovarian cancer families. We identified six pathogenic RAD51C mutations as well as 23 variants of uncertain clinical significance and one benign variant. Together, the study extends our knowledge of the RAD51C mutation spectrum and supports that RAD51C should be included in gene panel testing of individuals with high risk of breast and ovarian cancer.
authors.affiliation: Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Jønson
authors.affiliation: Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.
authors.forename: Lise B
authors.initials: LB
authors.lastname: Ahlborn
authors.affiliation: Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.
authors.forename: Ane Y
authors.initials: AY
authors.lastname: Steffensen
authors.affiliation: Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.
authors.forename: Malene
authors.initials: M
authors.lastname: Djursby
authors.affiliation: Department of Oncology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.
authors.forename: Bent
authors.initials: B
authors.lastname: Ejlertsen
authors.affiliation: Kennedy Center, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.
authors.forename: Susanne
authors.initials: S
authors.lastname: Timshel
authors.affiliation: Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.
authors.forename: Finn C
authors.initials: FC
authors.lastname: Nielsen
authors.affiliation: Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Gerdes
authors.affiliation: Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark. tvoh@rh.dk.
authors.forename: Thomas V O
authors.initials: TV
authors.lastname: Hansen
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D003718:Denmark; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D007438:Introns / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D012306:Risk
chemical_list: D004268:DNA-Binding Proteins; C448305:RAD51C protein, human
keywords: Breast cancer; In silico analysis; Mutation; Novel; Ovarian cancer; RAD51C