ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.817G>A (p.Val273Ile) (rs530814648)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236426 SCV000293804 uncertain significance not provided 2018-09-18 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.817G>A at the cDNA level, p.Val273Ile (V273I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). MSH2 c.817G>A was observed, in unknown phase, with MSH2 c.818T>A in an individual with a colorectal tumor demonstrating microsatellite instability and loss of MSH2 protein expression (Pigatto 2004, Sharp 2004). Due to the affected bases being adjacent, if the variants are in cis, this would result in MSH2 Val273Lys, and if in trans, this individual would be compound heterozygous for MSH2 Val273Ile and Val273Glu. However, c.817G>A or another nucleotide substitution resulting in MSH2 Val273Ile alone has not, to our knowledge, been reported in the literature. MSH2 Val273Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the connector domain (L?tzen 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 Val273Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000458697 SCV000548233 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 273 of the MSH2 protein (p.Val273Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs530814648, ExAC 0.02%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 246308). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine 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. 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.
Ambry Genetics RCV000564711 SCV000676076 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000564711 SCV000911234 likely benign Hereditary cancer-predisposing syndrome 2016-08-12 criteria provided, single submitter clinical testing

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