ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2439G>A (p.Met813Ile) (rs587781678)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129838 SCV000184654 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000168339 SCV000219028 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-02 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 813 of the MSH2 protein (p.Met813Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs587781678, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 141351). 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. 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.
GeneDx RCV000482932 SCV000565202 uncertain significance not provided 2016-06-02 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2439G>A at the cDNA level, p.Met813Ile (M813I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Met813Ile 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 Met813Ile occurs at a position that is conserved across species and is located within the ATPase domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Met813Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000129838 SCV000685044 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing

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