ClinVar Miner

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

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Total submissions: 6
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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 2018-05-25 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV000477198 SCV000548207 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-22 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
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002118 SCV001159968 uncertain significance not specified 2018-10-08 criteria provided, single submitter clinical testing The MSH2 c.481G>A; p.Val161Ile variant (rs149511545), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 182580). However, a different variant at this codon (p.Val161Asp) is reported in families with Lynch syndrome, and functional studies suggest the variant protein has deficient mismatch repair (MMR) activity and stability as well as abnormal subcellular localization (Bianchi 2018, Ollila 2006 and 2008). The p.Val161Ile variant is found in the general population with an overall allele frequency of 0.006% (17/277208 alleles) in the Genome Aggregation Database. The valine at codon 161 is well conserved, but computational analyses (SIFT, PolyPhen-2) predict the p.Val161Ile variant is tolerated. Due to limited information, the clinical significance of the p.Val161Ile variant is uncertain at this time. REFERENCES Bianchi F et al. A germline missense mutation in exon 3 of the MSH2 gene in a Lynch syndrome family: correlation with phenotype and localization assay. Fam Cancer. 2018 Apr;17(2):215-224. Ollila S et al. Mechanisms of pathogenicity in human MSH2 missense mutants. Hum Mutat. 2008 Nov;29(11):1355-63. Ollila S et al. Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein. Gastroenterology. 2006 Nov;131(5):1408-17.

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