ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.994C>T (p.Gln332Ter) (rs1555605074)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568757 SCV000674690 likely pathogenic Hereditary cancer-predisposing syndrome 2017-11-22 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)
Color RCV000568757 SCV000911558 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-10 criteria provided, single submitter clinical testing
GeneDx RCV000579112 SCV000680938 uncertain significance not provided 2017-03-27 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.994C>T at the cDNA level and p.Gln332Ter (Q332X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG). This variant has been reported in an individual with ovarian cancer with a family history of breast cancer (Kraus 2016). Due to the position of the variant, nonsense mediated decay is not expected to occur, but it might cause loss of normal protein function through protein truncation. RAD51C Gln332Ter was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Based on currently available information, we consider RAD51C Gln332Ter to be a variant of uncertain significance.
Invitae RCV000576180 SCV000676967 likely pathogenic Fanconi anemia, complementation group O 2018-12-08 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the RAD51C gene (p.Gln332*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 45 amino acids of the RAD51C protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 27616075). This variant is expected to cause the loss of 45 C-terminal amino acid residues from the RAD51C protein. 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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