ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2178G>C (p.Met726Ile) (rs587782396)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131413 SCV000186390 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000131413 SCV000537582 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-04 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000227062 SCV000592541 uncertain significance Lynch syndrome criteria provided, single submitter clinical testing
GeneDx RCV000767207 SCV000565200 uncertain significance not provided 2016-08-12 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2178G>C at the cDNA level, p.Met726Ile (M726I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Met726Ile 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 Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MSH2 Met726Ile occurs at a position that is conserved across species and is located within the ATPase domain (Lützen 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 Met726Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000524379 SCV000284140 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 726 of the MSH2 protein (p.Met726Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs587782396, ExAC 0.006%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 142341). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486473 SCV000601459 uncertain significance not specified 2017-06-08 criteria provided, single submitter clinical testing

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