ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.560T>G (p.Leu187Arg) (rs63751444)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076639 SCV000107674 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000822250 SCV000963043 likely pathogenic Hereditary nonpolyposis colon cancer 2018-07-20 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 187 of the MSH2 protein (p.Leu187Arg). 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 in several families affected with Lynch syndrome-associated cancers (PMID: 12624141, 21642682, 16395668, 19697156, 10995807). ClinVar contains an entry for this variant (Variation ID: 91135). Experimental studies have shown that this missense change impairs the mismatch repair activity of the MSH2 protein (PMID: 26951660, 19697156). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Variants that disrupt the p.Leu187 amino acid residue in MSH2 have been observed in affected individuals (PMID: 18951462, 16327991, 28422960, 17101317, 26951660). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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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