ClinVar Miner

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

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Total submissions: 8
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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 2019-03-06 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
Invitae RCV000199801 SCV000254385 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-03-04 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 C1). 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. 5
GeneDx RCV000656877 SCV000565194 uncertain significance not provided 2020-12-04 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29338072, 29596542, 30212499, 31159747)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656877 SCV000601434 uncertain significance not provided 2020-06-25 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129044 SCV000684938 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-14 criteria provided, single submitter clinical testing This missense variant replaces leucine with valine at codon 488 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/251314 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl RCV000662760 SCV000785554 uncertain significance Lynch syndrome I 2017-09-13 criteria provided, single submitter clinical testing
GeneKor MSA RCV000129044 SCV000822044 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000662760 SCV001135731 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing

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