ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2656G>T (p.Glu886Ter) (rs1230083633)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000501100 SCV000592554 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
Invitae RCV000808700 SCV000948815 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-01-02 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MSH2 gene (p.Glu886*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acids of the MSH2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Lynch syndrome-associated cancers in a family (PMID: 27413415). ClinVar contains an entry for this variant (Variation ID: 433904). This variant is expected to disrupt nearly the entire C-terminal portion of the MSH6 and MSH3 interaction domains of the MSH2 protein, as well as the helix-turn-helix domain (disrupted residues Glu886-Thr934) (PMID: 9774676, 18822302, 17531815). While functional studies have not been performed to directly test the effect of this variant on MSH2 protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. Other variant(s) that disrupt this region (p.Leu888Cysfs*4) have been determined to be pathogenic (PMID: 9222765, 9774676, 18822302, 17531815, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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