| Summary: | To identify candidate variants in <i>RAD51C</i> and <i>RAD51D</i> ovarian cancer (OC) predisposing genes by investigating French Canadians (FC) exhibiting unique genetic architecture. Candidates were identified by whole exome sequencing analysis of 17 OC families and 53 early-onset OC cases. Carrier frequencies were determined by the genetic analysis of 100 OC or HBOC families, 438 sporadic OC cases and 1025 controls. Variants of unknown function were assayed for their biological impact and/or cellular sensitivity to olaparib. <i>RAD51C</i> c.414G>C;p.Leu138Phe and c.705G>T;p.Lys235Asn and <i>RAD51D</i> c.137C>G;p.Ser46Cys, c.620C>T;p.Ser207Leu and c.694C>T;p.Arg232Ter were identified in 17.6% of families and 11.3% of early-onset cases. The highest carrier frequency was observed in OC families (1/44, 2.3%) and sporadic cases (15/438, 3.4%) harbouring <i>RAD51D</i> c.620C>T versus controls (1/1025, 0.1%). Carriers of c.620C>T (<i>n</i> = 7), c.705G>T (<i>n</i> = 2) and c.137C>G (<i>n</i> = 1) were identified in another 538 FC OC cases. <i>RAD51C</i> c.705G>T affected splicing by skipping exon four, while RAD51D p.Ser46Cys affected protein stability and conferred olaparib sensitivity. Genetic and functional assays implicate <i>RAD51C</i> c.705G>T and <i>RAD51D</i> c.137C>G as likely pathogenic variants in OC. The high carrier frequency of <i>RAD51D</i> c.620C>T in FC OC cases validates previous findings. Our findings further support the role of <i>RAD51C</i> and <i>RAD51D</i> in hereditary OC.
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