A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect

Abstract

Background: RAD51C is important in DNA repair and individuals with pathogenic RAD51C variants have increased risk of hereditary breast and ovarian cancer syndrome (HBOC), an autosomal dominant genetic predisposition to early onset breast and/or ovarian cancer. Methods: Five female HBOC probands sequenced negative for moderate-and high-risk genes but shared a recurrent variant of uncertain significance in RAD51C (NM_058216.3: c.571 + 4A > G). Participant recruitment was followed by haplotype and case/control analyses, RNA splicing analysis, gene and protein expression assays, and Sanger sequencing of tumors. Results: The RAD51C c.571 + 4A > G variant segregates with HBOC, with heterozygotes sharing a 5.07 Mbp haplotype. RAD51C c.571 + 4A > G is increased ~52-fold in the Newfoundland population compared with the general Caucasian population and positive population controls share disease-associated alleles, providing evidence of a founder effect. Splicing analysis confirmed in silico predictions that RAD51C c.571 + 4A > G causes exon 3 skipping, creating an immediate premature termination codon. Gene and protein expression were significantly reduced in a RAD51C c.571 + 4G > A heterozygote compared with a wild-type relative. Sanger sequencing of tumors from two probands indicates loss-of-heterozygosity, suggesting loss of function. Conclusion: The RAD51C c.

Specialty Care and Counselling about Hereditary Cancer Risk Improves Adherence to Cancer Screening and Prevention in Newfoundland and Labrador Patients with BRCA1/2 Pathogenic Variants: A Population-Based Retrospective Cohort Study

“…The frequency of BRCA1 and BRCA2 PVs observed in this cohort and their recurrence among multiple families is consistent with NL's known ancestry [28] and suggests evidence for multiple founder effects [40]. Other founder effects predisposing to hereditary cancers in the NL population have been described [41][42][43]. As NL has the highest and second highest incidence rates of female BC and OC in Canada, respectively [44], identifying and understanding the contributions of these BRCA1/2 PVs to hereditary BC and OC in NL is critical.…”

Impact of Breast Cancer Screening on 10-Year Net Survival in Canadian Women Age 40-49 Years

“…This might have been the case with Newfoundland and Labrador, which is noted to have a lower NS despite higher screening activity, perhaps because of known founder mutations. 48 The relationship between screening and NS might have been underestimated as the CCHS percentages were for biennial screening. Optimal BC screening in women age 40-49 years should be annual given the more rapid growth of BCs in women with higher levels of hormones.…”