ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.1005C>A (p.Cys335Ter) (rs759292615)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220031 SCV000275300 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000657741 SCV000779492 uncertain significance not provided 2017-11-27 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.1005C>A at the cDNA level and p.Cys335Ter (C335X) at the protein level. The substitution creates a nonsense variant, which changes a Cysteine to a premature stop codon (TGC>TGA). This variant has not, to our knowledge, been reported in the literature. RAD51C Cys335Ter results in the loss of 42 amino acids at the end of the protein, which might affect normal function. However, due to the location of the newly created nonsense codon, the transcript is not expected to undergo nonsense-mediated decay and could therefore encode a truncated protein that retains some function. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on currently available evidence, we consider RAD51C Cys335Ter to be a variant of uncertain significance.
Invitae RCV000232127 SCV000291208 likely pathogenic Fanconi anemia, complementation group O 2018-10-29 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the RAD51C gene (p.Cys335*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 42 amino acids of the RAD51C protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database (rs759292615). This variant has not been reported in the literature in individuals with RAD51C-related disease. ClinVar contains an entry for this variant (Variation ID: 231450). This variant is expected to cause the loss of 42 C-terminal amino acid residues from the RAD51C protein. While the effects 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. Experimental studies have shown that deletion of the last 11 amino acid residues leads to cellular mislocalization of the RAD51C 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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