ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2298A>G (p.Ile766Met) (rs1064795116)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484269 SCV000570598 uncertain significance not provided 2016-06-08 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2298A>G at the cDNA level, p.Ile766Met (I766M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATA>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ile766Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ile766Met occurs at a position that is conserved across species and is located within the ATPase domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Ile766Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000527665 SCV000625367 uncertain significance Hereditary nonpolyposis colon cancer 2018-01-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 766 of the MSH2 protein (p.Ile766Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000563540 SCV000662222 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-26 criteria provided, single submitter clinical testing Insufficient evidence

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