In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer.
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.
RAD51Cc.-13_14del27 was observed in one familial breast cancer case and c.774delT in one unselected ovarian cancer case, thus confirming that RAD51C mutations are implicated in breast and ovarian cancer predisposition, although their overall frequency seems to be low.
We have screened RAD51C sequence variants by HRMA in 492 breast cancer patients with family history of breast and/or ovarian cancer that were previously tested negative for BRCA1/2.
Our data confirm a consistent but low frequency (2/335 families) of inactivating RAD51C mutations among families with a history of both breast and ovarian cancer and an absence of mutations among breast cancer only families (0/1,053 families).
In the Finnish population, we have identified two founder mutations in RAD51C that increase the risk of ovarian cancer but not breast cancer in the absence of ovarian cancer.
Deleterious mutations in the RAD51C gene, which encodes a DNA double-strand break repair protein, have been reported to confer high-penetrance susceptibility to both breast and ovarian cancer.
An increased cancer risk has been firmly established for carriers of mutations in FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, RAD51C/FANCO and link the FA pathway to inherited breast and ovarian cancer.
Our analyses with pathological mutants of RAD51C that were identified in FA and breast and ovarian cancers reveal that RAD51C regulates HR and DNA damage signaling distinctly.
There is ongoing debate whether pathogenic RAD51C alterations increase the relative risk for BC in addition to that for OC, which was estimated to be 5.88 (95% confidence interval = 2.91 to 11.88; P = 7.65 × 10(-7)).
Our results support that RAD51C is a rare breast and ovarian cancer susceptibility gene and may contribute to a small fraction of families including breast and ovarian cancer cases and families with only breast cancer.
Deleterious and missense mutations of RAD51C have recently been suggested to modulate the individual susceptibility to hereditary breast and ovarian cancer and unselected ovarian cancer, but not unselected breast cancer (BrC).
Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D.
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.
Although the cumulative frequency of RAD51C and RAD51D truncating mutations in our patients was lower than that of the BRCA1 and BRCA2 genes, it may explain OC susceptibility in approximately 3% of high-risk OC patients.