Abstract
BRCA1 and BRCA2 are the most well-known breast cancer susceptibility genes. Additional genes involved in DNA repair have been identified as predisposing to breast cancer. One such gene, RAD51C, is essential for homologous recombination repair. Several likely pathogenic RAD51C mutations have been identified in BRCA1- and BRCA2-negative breast and ovarian cancer families. We performed complete sequencing of RAD51C in germline DNA of 286 female breast and/or ovarian cancer cases with a family history of breast and ovarian cancers, who had previously tested negative for mutations in BRCA1 and BRCA2. We screened 133 breast cancer cases, 119 ovarian cancer cases, and 34 with both breast and ovarian cancers. Fifteen DNA sequence variants were identified; including four intronic, one 5′ UTR, one promoter, three synonymous, and six non-synonymous variants. None were truncating. The in-silico SIFT and Polyphen programs were used to predict possible pathogenicity of the six non-synonomous variants based on sequence conservation. G153D and T287A were predicted to be likely pathogenic. Two additional variants, A126T and R214C alter amino acids in important domains of the protein such that they could be pathogenic. Two-hybrid screening and immunoblot analyses were performed to assess the functionality of these four non-synonomous variants in yeast. The RAD51C-G153D protein displayed no detectable interaction with either XRCC3 or RAD51B, and RAD51C-R214C displayed significantly decreased interaction with both XRCC3 and RAD51B (p<0.001). Immunoblots of RAD51C-Gal4 activation domain fusion peptides showed protein levels of RAD51C-G153D and RAD51C-R214C that were 50% and 60% of the wild-type, respectively. Based on these data, the RAD51C-G153D variant is likely to be pathogenic, while the RAD51C- R214C variant is hypomorphic of uncertain pathogenicity. These results provide further support that RAD51C is a rare breast and ovarian cancer susceptibility gene.
Highlights
Breast cancer is the most common cancer worldwide and the second leading cause of cancer death among women in the United States [1]
RAD51C is involved in two specific subcomplexes, one with XRCC2, RAD51B, and RAD51D, and the other with XRCC3 [18], and has multiple functions in the DNA damage response and the maintenance of genomic stability [19]
Of which we selected four non-synonymous variants for functional studies; RAD51C-G153D and RAD51C-T287A because they alter highly conserved amino acid residues, RAD51C-A126T because it alters an amino acid in the Walker A box, and RAD51C-R214C because it alters an amino acid that separates a beta-strand from an alphahelix
Summary
Breast cancer is the most common cancer worldwide and the second leading cause of cancer death among women in the United States [1]. Mutations in CHEK2, ATM, BRIP1, and PALB2, genes involved in genome maintenance and homologous recombination, have been identified as predisposing to breast cancer; they only account for a small portion of the hereditary cases [4]. RAD51C, essential for homologous recombination repair, has been reported to be a rare hereditary breast and ovarian cancer susceptibility gene and several pathogenic RAD51C mutations have been identified in BRCA1- and BRCA2-negative hereditary breast and ovarian cancer families (HBOC) [5]. Several pathogenic variants were observed in five studies [5,7,8,9,10] with all in HBOC families or in ovarian cancer cases. There are multiple studies and evidence that RAD51C is a rare ovarian cancer predisposition gene important in both breast and ovarian cancers in HBOC families. More studies are needed to determine its penetrance and the role it plays in these cancers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
