ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1729A>G (p.Ile577Val) (rs774985655)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484349 SCV000571245 uncertain significance not provided 2016-08-04 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1729A>G at the cDNA level, p.Ile577Val (I577V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ile577Val 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 Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ile577Val occurs at a position that is conserved across species and is located within the lever domain and the region of interaction with MSH6 and MSH3 (Lützen 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 Ile577Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000581019 SCV000684969 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Invitae RCV000630236 SCV000751192 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 577 of the MSH2 protein (p.Ile577Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs774985655, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 421910). 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.

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