ClinVar Miner

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

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Total submissions: 7
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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 colorectal neoplasms 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 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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985811 SCV001134365 pathogenic not provided 2019-01-25 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Integrated Genetics/Laboratory Corporation of America RCV001194033 SCV001363269 pathogenic Hereditary nonpolyposis colon cancer 2019-10-29 criteria provided, single submitter clinical testing Variant summary: MSH2 c.484G>A (p.Gly162Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251482 control chromosomes (gnomAD). c.484G>A has been reported in the literature in multiple individuals affected with colon cancer and HNPCC (Loader_2002, Ollila_2006, Belvederesi_2008, Thompson_2013, Brennan_2017, Rossi_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication, Ollila_2006, reports this variant had effects on protein stability, localization and DNA repair activity. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic

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