Submission Details

RAD51C is one of the more than twenty Fanconi anemia (FA) or FA-like genes known to cause autosomal recessive FA characterized by bone marrow failure, developmental abnormalities, and cancer predisposition. Biallelic variant in RAD51C was first identified in a patient with Fanconi anemia complementation group O (FANCO) in 2010 by Vaz et al. (PMID: 20400963). RAD51C is a member of the RAD51 gene family. The protein of RAD51 family members are known to be involved in the homologous recombination and repair of DNA. RAD51C protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Monoallelic RAD51C variants were also linked to autosomal dominant familial ovarian cancer and triple negative breast cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have split autosomal dominant triple negative breast cancer and ovarian cancer into separate curations due to phenotypic variability and different inheritance patterns. Therefore, this curation solely focuses on autosomal recessive FANCO. Three variants (1 intronic variant predicted to result in splice effect and 2 missense variants) identified in 2 families are included in this curation (2.6 points; PMIDs: 20400963, 29278735). The mechanism of pathogenicity appears to be loss of function (LOF). This gene-disease relationship is also supported by experimental evidence including animal models and biomedical function studies (2.5 points; PMIDs: 22167183, 30540754, 36906610). The cells with loss of RAD51C or expressing RAD51C variants exhibited a marked increase in the frequency of interstrand cross-links and double strand breaks. Knockout zebrafish model exhibited a partial female sex reversal. This reversal may illustrate that the RAD51C gene is important for gonadogenesis and may reflect the commonly observed hypogonadism in FA probands. Mice with double knockout of Rad51c and Brca2 demonstrates phenotypes seen in FA patients including DNA replication instability, higher spontaneous chromosomal aberrations, bone marrow failure, leukemia, reduced survivability. Combination of genetic and experimental evidence has not demonstrated convincing definitive validity of RAD51C gene in inherited FANCO. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the role of RAD51C in FANCO.

This gene-disease pair was originally evaluated as moderate by the General Gene Curation GCEP on 1/5/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 07/28/2023 (SOP Version 9).