ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.481G>A (p.Val161Ile) (rs149511545)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212587 SCV000211209 uncertain significance not provided 2018-05-29 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.481G>A at the cDNA level, p.Val161Ile (V161I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH2 Val161Ile was observed at an allele frequency of 0.06% (15/24030) in individuals of African ancestry in large population cohorts (Lek 2016). MSH2 Val161Ile is located in the connector domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Val161Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160612 SCV000216013 likely benign Hereditary cancer-predisposing syndrome 2017-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Invitae RCV000477198 SCV000548207 uncertain significance Hereditary nonpolyposis colon cancer 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 161 of the MSH2 protein (p.Val161Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs149511545, ExAC 0.05%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182580). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Val161 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been observed in individuals with MSH2-related conditions (PMID: 11726306, 28785832), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000212587 SCV000860256 uncertain significance not provided 2018-03-30 criteria provided, single submitter clinical testing
Color RCV000160612 SCV000903871 likely benign Hereditary cancer-predisposing syndrome 2016-04-20 criteria provided, single submitter clinical testing

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