Abstract
BackgroundRAD51C 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.MethodsFive 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.ResultsThe 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.ConclusionThe RAD51C c.571 + 4A > G variant affects mRNA splicing and should be re‐classified as pathogenic according to American College of Medical Genetics and Genomics guidelines.
Highlights
Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant genetic predisposition to early onset breast cancer (BC) and/or ovarian cancer (OC)
25% of hereditary breast and ovarian cancer syndrome (HBOC) cases are attributed to pathogenic variants in BRCA1 (OMIM: 113705) and BRCA2 (OMIM: 600185), which encode proteins involved in homologous recombination (HR) DNA repair (Nielsen, van Overeem Hansen, & Sorensen, 2016)
We have determined that a recurrent RAD51C splicing variant (c.571 + 4A > G) predisposes to both BC and OC in the Newfoundland and Labrador (NL) population due to strong founder effect
Summary
Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant genetic predisposition to early onset breast cancer (BC) and/or ovarian cancer (OC). Multiple studies have identified an association between RAD51C pathogenic variants and OC, or families with BC and OC in different populations (Blanco et al, 2014; Clague et al, 2011; Eoh et al, 2018; Jonson et al, 2016; Loveday et al, 2012; Lu et al, 2018; Meindl et al, 2010; Neidhardt et al, 2017; Osorio et al, 2012; Pang et al, 2011; Pelttari et al, 2011, 2018; Romero et al, 2011; SanchezBermudez et al, 2018; Schnurbein et al, 2013; Song et al, 2015; Sung et al, 2017; Thompson et al, 2012; Vuorela et al, 2011). Pedigree construction, haplotype analysis, and functional studies revealed a dominant-acting RAD51C c.571 + 4A > G splicing variant residing on a shared HBOC-associated haplotype that increases the risk for BC in addition to OC
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