One of five RAD51-related genes, RAD51C has been reported to be linked to both Fanconi anemia–like disorders and familial breast and ovarian cancers. The literature, however, has produced contradictory findings. In a study of 480 German families characterized by breast and ovarian cancers who were negative for BRCA1 and BRCA2 mutations, six monoallelic mutations in RAD51C were found (frequency of 1.3%). No mutations were found in breast cancer–only families or in healthy controls. Another study screened 286 BRCA1/2-negative patients with breast cancer and/or ovarian cancer and found one likely deleterious mutation in RAD51C-G153D.RAD51C mutations have also been reported in Australian, Finnish, and Spanish non-BRCA1/2 ovarian cancer–only and breast/ovarian cancer families, and in unselected ovarian cancer cases.[82,83,84,85] Three additional studies were unable to confirm an association between the RAD51C gene and hereditary breast cancer or ovarian cancer.[69,86,87]
In addition to RAD51C mutation carriers, there are other RAD51 paralogs, including RAD51D and RAD51L1, that may be associated with breast and/or ovarian cancer risk,[88,89,90,91] although the clinical significance of these findings is unknown.
In addition to germline mutations, different polymorphisms of RAD51 have been hypothesized to have reduced capacity to repair DNA defects, resulting in increased susceptibility to familial breast cancer. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) pooled data from 8,512 BRCA1 and BRCA2 mutation carriers and found evidence of an increased risk of breast cancer among women who were BRCA2 carriers and who were homozygous for CC at the RAD51 135G→C SNP (hazard ratio, 1.17; 95% CI, 0.91–1.51).
Several meta-analyses have investigated the association between the RAD51 135G→C polymorphism and breast cancer risk. There is significant overlap in the studies reported in these meta-analyses, significant variability in the characteristics of the populations included, and significant methodologic limitations to their findings.[93,94,95,96] A meta-analysis of nine epidemiologic studies involving 13,241 cases and 13,203 controls of unknown BRCA1/2 status found that women carrying the CC genotype had an increased risk of breast cancer compared to women with the GG or GC genotype (OR [odds ratio], 1.35; 95% CI, 1.04–1.74). A meta-analysis of 14 case-control studies involving 12,183 cases and 10,183 controls confirmed an increased risk only for women who were known BRCA2 carriers (OR, 4.92; 95% CI, 1.10–21.83). Another meta-analysis of 12 studies included only studies of known BRCA-negative cases and found no association between RAD51 135G→C and breast cancer.
In summary, among this conflicting data there is substantial evidence for a weak association between germline mutations in RAD51C and breast cancer and ovarian cancer. There is also evidence of an association between polymorphisms in RAD51 135G→C among women with homozygous CC genotypes and breast cancer, particularly among BRCA2 carriers. These associations are plausible given the known role of RAD51 in the maintenance of genomic stability.