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Low- and Moderate-Penetrance Genes Associated With Breast and / or Ovarian Cancer

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    RAD51

    RAD51 and the family of RAD51-related genes, also known as RAD51 paralogs, are thought to encode proteins that are involved in DNA damage repair through homologous recombination and interaction with numerous other DNA repair proteins, including BRCA1 and BRCA2. RAD51 protein plays a central role in single-strand annealing in the DNA damage response. RAD51 recruitment to break sites and recombinational DNA repair depend on the RAD51 paralogs, although their precise cellular functions are poorly characterized.[78] Mutations in these genes are thought to result in loss of RAD51 focus formation in response to DNA damage.[79]

    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%).[80] 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.[81]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).[92]

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