ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.646A>G (p.Ile216Val) (rs63749936)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216132 SCV000276982 likely benign Hereditary cancer-predisposing syndrome 2016-07-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Invitae RCV000541467 SCV000625448 uncertain significance Hereditary nonpolyposis colon cancer 2017-05-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 216 of the MSH2 protein (p.Ile216Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with polyps (PMID: 11726306). ClinVar contains an entry for this variant (Variation ID: 91171). An algorithm developed specifically for the MSH2 gene (PMID: 22290698), suggests that this missense change is likely to be tolerated. Additionally, the valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant has uncertain impact on MSH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000216132 SCV000908281 likely benign Hereditary cancer-predisposing syndrome 2017-06-08 criteria provided, single submitter clinical testing

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