ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.709A>G (p.Ile237Val) (rs63751307)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115540 SCV000149449 uncertain significance not provided 2016-07-21 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.709A>G at the cDNA level, p.Ile237Val (I237V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant was observed in an individual with a poorly differentiated, microsatellite instable colon cancer diagnosed at the age of 66 and with no family history of cancer (Chaksangchaichot 2007). MSH2 Ile237Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution and is unlikely to affect protein integrity. MSH2 Ile237Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species, and is located in the connector domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Ile237Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000543104 SCV000625455 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-10-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 237 of the MSH2 protein (p.Ile237Val). The isoleucine residue is moderately 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 not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 127651). 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 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. 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 RCV000567353 SCV000669827 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing Insufficient evidence

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