ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.484G>A (p.Gly162Arg) (rs63750624)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076608 SCV000107644 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000524412 SCV000548190 likely pathogenic Hereditary nonpolyposis colon cancer 2018-06-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 162 of the MSH2 protein (p.Gly162Arg). 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 (rs63750624, ExAC no frequency). This variant has been reported in several individuals affected with Lynch syndrome or suspected Lynch syndrome (PMID: 17101317, 18781619, 12537652). ClinVar contains an entry for this variant (Variation ID: 91105). Experimental studies have shown that this missense change causes an abnormal cellular localization defect and results in a loss of mismatch repair activity in vitro (PMID: 18951462, 17101317, 22949387, 18781619, 24362816). In addition, based on a multifactorial likelihood algorithm developed to assess the clinical significance of mismatch repair gene alterations, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). In summary, this variant is absent in the general population, alters protein function, and has been reported in individuals with Lynch syndrome. However, segregation with disease has not been reported. For these reasons, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000491163 SCV000580414 pathogenic Hereditary cancer-predisposing syndrome 2018-03-23 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,Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Counsyl RCV000662882 SCV000785789 pathogenic Lynch syndrome I 2017-11-28 criteria provided, single submitter clinical testing
Color RCV000491163 SCV000905218 pathogenic Hereditary cancer-predisposing syndrome 2017-11-10 criteria provided, single submitter clinical testing

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