ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1462T>G (p.Leu488Val) (rs587781314)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129044 SCV000172956 likely benign Hereditary cancer-predisposing syndrome 2018-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),In silico models in agreement (benign)
Color RCV000129044 SCV000684938 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing
Counsyl RCV000662760 SCV000785554 uncertain significance Lynch syndrome I 2017-09-13 criteria provided, single submitter clinical testing
GeneDx RCV000656877 SCV000565194 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1462T>G at the cDNA level, p.Leu488Val (L488V) at the protein level, and results in the change of a Leucine to a Valine (TTG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Leu488Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Leu488Val occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located within the Clamp domain and a region of interaction with MSH6 and MSH3 (L?tzen 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 Leu488Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000129044 SCV000822044 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000199801 SCV000254385 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 488 of the MSH2 protein (p.Leu488Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs587781314, ExAC 0.003%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 140843). 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 C15"). 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 RCV000485646 SCV000601434 uncertain significance not specified 2017-06-16 criteria provided, single submitter clinical testing

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