ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1784T>G (p.Leu595Arg) (rs786201590)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163932 SCV000214528 pathogenic Hereditary cancer-predisposing syndrome 2017-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence
Invitae RCV000554840 SCV000625315 uncertain significance Hereditary nonpolyposis colon cancer 2017-06-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 595 of the MSH2 protein (p.Leu595Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Lynch syndrome (PMID: 184645). ClinVar contains an entry for this variant (Variation ID: 184645). 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 disruptive, 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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