ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1765G>A (p.Val589Ile) (rs1064793981)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000581059 SCV000684972 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing
GeneDx RCV000766532 SCV000567511 uncertain significance not provided 2015-08-03 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1765G>A at the cDNA level, p.Val589Ile (V589I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Val589Ile 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 Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MSH2 Val589Ile occurs at a position that is not conserved and is located within the Level domain and region of interaction with MSH6 and MSH3 (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 Val589Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000551068 SCV000625309 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-28 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 589 of the MSH2 protein (p.Val589Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 419601). 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: "Tolerated"; PolyPhen-2: "Possibly 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000479480 SCV000731287 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing The p.Vale589Ile variant in MSH2 has not been previously reported in individuals with colon cancer and was absent from large population studies. This variant w as detected in a cohort of 20,000 samples referred to Ambry Genetics for multige ne hereditary-cancer testing (Mu 2016, supplemental table 3); however, no clinic al details are provided. Valine (Val) at position 589 is not well conserved in e volution and most computational prediction tools suggest that it does not impact the protein though this information is not predictive enough to rule out pathog enicity. In summary, the clinical significance of the p.Vale589Ile variant in MS H2 variant is uncertain.

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