ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.10C>T (p.Gln4Ter)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000780451 SCV000917707 likely pathogenic Lynch syndrome 2018-01-08 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.10C>T (p.Gln4X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Cys176X, p.Gln344X, p.Arg389X, etc.). This variant is absent in 212810 control chromosomes (gnomAD). This variant has been reported in one breast cancer patient (Sun_2017). Taken together, this variant is classified as likely pathogenic.
Invitae RCV000701344 SCV000830142 uncertain significance Hereditary nonpolyposis colon cancer 2018-03-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln4*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 28724667). Reports on variants that affect the MSH2 initiator codon, c.1A>C and c.1A>T, indicate that Met26 may serve as an alternate initiator codon (PMID: 21837758, 9718327, 18781192). An experimental study of a recombinant MSH2 protein lacking the first 25 amino acid residues has shown that the truncated protein remains partially functional (PMID: 21837758). The clinical significance of these findings is unknown. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). However, there is uncertainty with this variant as to whether an alternate in-frame methionine, downstream of the initiator codon, could potentially rescue translation initiation. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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