ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2047G>A (p.Gly683Arg) (rs267607995)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076370 SCV000107397 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000132039 SCV000187098 pathogenic Hereditary cancer-predisposing syndrome 2018-08-07 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Other data supporting pathogenic classification
Invitae RCV000524373 SCV000253804 pathogenic Hereditary nonpolyposis colon cancer 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 683 of the MSH2 protein (p.Gly683Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a Lynch syndrome family (PMID: 18931482), and has been observed in three other unrelated individuals affected with MSH2-related cancers (PMID: 11606497, 19731080, 26248088, Invitae database). ClinVar contains an entry for this variant (Variation ID: 90868). Experimental studies have shown that this missense change disrupts protein stability and mismatch repair activity in vitro (PMID: 23690608). In addition, this missense change is located in the Walker A ATPase domain of the MSH2 protein, where a significant number of previously reported deleterious MSH2 missense mutations are found (PMID: 23690608). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202225 SCV000257166 uncertain significance not specified no assertion criteria provided research

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