ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1A>T (p.Met1Leu) (rs267607911)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076336 SCV000107360 uncertain significance Lynch syndrome 2019-06-21 reviewed by expert panel curation Insufficient evidence
Invitae RCV000076336 SCV000254398 uncertain significance Lynch syndrome 2015-04-22 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the MSH2 mRNA. It is predicted to lead to a truncated protein as a result of alternate initiator methionine. This variant has been reported in the literature in a patient affected with colon cancer (PMID: 9718327) and is not present in population databases. In vitro assays of patient RNA showed that this variant results in translation initiation at codon 26, leading to a less stable transcript and the loss of 25 N-terminal amino acid residues from the MSH2 protein (PMID: 9718327). Functional analyses of a recombinant MSH2 protein lacking the N-terminal 25 amino acids showed that the truncated protein was capable of binding to MSH6 and had slightly reduced activity compared to the wild type complex. The clinical significance of these findings is unknown. In summary, this is a rare variant with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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