RAD51C mutation screening in high-risk patients from Serbian hereditary breast/ovarian cancer families

Background: In 2010 an important finding was published showing that heterozygous mutations in RAD51C were highly penetrant and were able to confer an increased risk for breast and ovarian cancers. The role of possible third high penetrance breast cancer susceptibility gene was assigned to RAD51C.

Objective: Because of its rising importance in breast cancer development and the lack of information about RAD51C in Slavic populations, our goal was to identify potential population specific mutations in this gene in order to determine more detailed genetic screening strategy and breast cancer risk assessment.

Methods: The study included 55 females from Serbian hereditary breast/ovarian cancer families negative for sequence alterations and large genomic rearrangements in BRCA1/2 genes. Whole coding region and exon-intron boundaries of RAD51C were analyzed by dHPLC. All mutations were confirmed by Sanger sequencing. SIFT and Polyphen were used to predict possible impact of non-synonymous variants.

Results: We found 5 variants in RAD51C including two missense, one intronic, one in the 5'UTR and one variant in the promoter region of the gene. Three detected variants are common - c.1-118G>A (rs16943176, MAF = 0,203); c.1-26C>T (rs12946397, MAF = 0,207) and c.904+34T>C (rs28363318, MAF = 0,186). We detected two missense variants, c.790G>A (p.Gly264Ser) in exon 5 and c.859A>G (p.Thr287Ala) in exon 6. Both of them were previously shown to exhibit reduced protein function but their contribution to cancer risk is still unknown.

Conclusions: Although the initial reports implied that RAD51C might be promising candidate for next high penetrance breast cancer susceptibility gene, lack of confirmation suggested that RAD51C mutations are not as common as expected. Our study did not reveal truncating mutations in RAD51C suggesting that other breast cancer susceptibility genes may account for the increased susceptibility in our cohort of high-risk BRCA1/2 negative families.