ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2662del (p.Leu888fs) (rs63751007)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076537 SCV000107566 pathogenic Lynch syndrome I 2018-06-13 reviewed by expert panel curation codon 888 is cutoff for truncating variants in the last exon of MSH2
Ambry Genetics RCV000491264 SCV000580557 pathogenic Hereditary cancer-predisposing syndrome 2019-07-02 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000629927 SCV000750883 pathogenic Hereditary nonpolyposis colon cancer 2018-10-09 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MSH2 gene (p.Leu888Cysfs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acids of the MSH2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with colorectal cancer (PMID:21879275). Also, it has also been shown to segregate with Lynch syndrome-associated cancers in a single family (PMID: 9222765, 8640829). This variant is also known as codon 888delC and c.2662del in the literature. ClinVar contains an entry for this variant (Variation ID: 91035). While this variant is not expected to result in nonsense mediated decay, it 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 Ile888-Thr934) (PMID: 9774676, 18822302, 17531815). Although functional studies have not been done for this particular variant, loss of the C-terminal region of the protein likely impairs MSH2 function (PMID: 9774676, 18822302, 17531815). This suggests that deletion of this region of the MSH2 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

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