ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1087G>T (p.Val363Leu) (rs377345366)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479898 SCV000566532 uncertain significance not provided 2018-09-24 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1087G>T at the cDNA level, p.Val363Leu (V363L) at the protein level, and results in the change of a Valine to a Leucine (GTG>TTG). This variant was observed in an individual diagnosed with leukemia and another with breast cancer (Zhang 2015, Yehia 2018). MSH2 Val363Leu was observed at an allele frequency of 0.03% (7/24020) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the lever domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Val363Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000561329 SCV000662213 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000629790 SCV000750746 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 363 of the MSH2 protein (p.Val363Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs377345366, ExAC 0.03%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 419016). 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: "Benign"; Align-GVGD: "Class C25"). 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.
Color RCV000561329 SCV000908294 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing

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