ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.1057_1066del (p.Ser353fs) (rs1064792966)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570589 SCV000667117 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000456930 SCV000550226 likely pathogenic Fanconi anemia, complementation group O 2018-05-01 criteria provided, single submitter clinical testing This sequence change deletes 10 nucleotides from exon 9 of the RAD51C mRNA (c.1057_1066delTCTGCATGTT), causing a frameshift at codon 353. This creates a premature translational stop signal in the last exon of the RAD51C mRNA (p.Ser353Hisfs*8). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acids of the RAD51C protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RAD51C-related disease. ClinVar contains an entry for this variant (Variation ID: 409862). While the effect of this particular sequence change on RAD51C function has not been tested, the C-terminal region of RAD51C is known to contain a nuclear localization signal, and the deletion of 11 C-terminal residues leads to cellular mislocalization of the protein, as well as reduced mitomycin C resistance compared to the wild-type protein (PMID: 12966089). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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