ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2063T>G (p.Met688Arg) (rs63749993)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491088 SCV000580468 pathogenic Hereditary cancer-predisposing syndrome 2017-06-21 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,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other strong data supporting pathogenic classification,Good segregation with disease (lod 1.5-3 = 5-9 meioses)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076376 SCV000592530 pathogenic Lynch syndrome 2012-09-24 criteria provided, single submitter clinical testing
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076376 SCV000107403 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000524375 SCV000548177 pathogenic Hereditary nonpolyposis colon cancer 2017-11-06 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 688 of the MSH2 protein (p.Met688Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (rs63749993, ExAC no frequency). This variant has been reported in several families affected with Lynch syndrome (PMID: 10080150, 15075785, 20010080, 22739024, 21239990, 21225464). It is considered a founder mutation in several families from the Island of Tenerife (Canary Islands) (PMID: 15075785, 20010080, 22739024). ClinVar contains an entry for this variant (Variation ID: 90874). An experimental study has shown that this missense change results in a defective MSH2 protein. The variant protein lacks normal ATPase function, displays reduced mismatch DNA-binding activity, and inhibits mismatch repair activity in a dominant-negative fashion in vitro when mixed with wild-type MSH2-MSH6 heterodimers (PMID: 22739024). For these reasons, this variant has been classified as Pathogenic.

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