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Mol Genet Genomic Med ; 8(2): e1070, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31782267

RESUMO

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.571 + 4A > G variant affects mRNA splicing and should be re-classified as pathogenic according to American College of Medical Genetics and Genomics guidelines.


Assuntos
Proteínas de Ligação a DNA/genética , Efeito Fundador , Síndrome Hereditária de Câncer de Mama e Ovário/genética , População/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Genes Dominantes , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Terra Nova e Labrador , Splicing de RNA
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