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 2018-10-15 criteria provided, single submitter clinical testing 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 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-07-30 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 observed to segregate in a Lynch syndrome family (External communication), and identified in several individuals affected with clinical features of Lynch syndrome (PMID: 23990280, 12454801, Invitae). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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