ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.493T>G (p.Tyr165Asp) (rs587779163)

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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) RCV000076614 SCV000107650 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability between 0.95-0.99
Invitae RCV000630010 SCV000750966 likely pathogenic Hereditary nonpolyposis colon cancer 2018-04-13 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with aspartic acid at codon 165 of the MSH2 protein (p.Tyr165Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family with Lynch syndrome (PMID: 24501230), as well as families with suspected Lynch syndrome (PMID: 24501230, Invitae). ClinVar contains an entry for this variant (Variation ID: 91111). Experimental studies have shown that this missense change results in reduced MSH2 and MSH6 protein expression (PMID: 24501230, 26951660) and disrupted mismatch repair activity (PMID: 22102614, 24501230, 26951660). 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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