ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.491G>A (p.Gly164Glu) (rs786204082)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000240465 SCV000299172 likely pathogenic Lynch syndrome 2018-11-22 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability >0.99 but only 1 family so classification is reduced to class 4
Invitae RCV000167977 SCV000218625 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-07-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 164 of the MSH2 protein (p.Gly164Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with colon cancer in the InSiGHT Database, indicating segregation with disease in their family (PMID: 23443670). This variant has also been observed in 2 individuals with early onset colorectal cancer from one family (Invitae). In addition, it has been observed in several individuals with diagnosed or suspected Lynch syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 188119). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). A different missense substitution at this codon (p.Gly164Arg) has been determined to be pathogenic (PMID: 1710317, 18951462, 15849733). This suggests that the glycine residue is critical for MSH2 protein function and that other missense substitutions at this position may also be pathogenic. 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.
Ambry Genetics RCV000223301 SCV000276729 pathogenic Hereditary cancer-predisposing syndrome 2019-06-10 criteria provided, single submitter clinical testing The p.G164E pathogenic mutation (also known as c.491G>A), located in coding exon 3 of the MSH2 gene, results from a G to A substitution at nucleotide position 491. The glycine at codon 164 is replaced by glutamic acid, an amino acid with similar properties. This mutation was detected in an individual whose colon tumor displayed absent MSH2/MSH6 protein staining by immunohistochemistry and had a family history that met Amsterdam criteria. Furthermore, the alteration showed moderate segregation with disease in this family (Ambry internal data). This mutation was identified in an individual with urothelial cancer who also met Amsterdam criteria II; MSH2 and MSH6 expression was also lost upon IHC analysis (Ambry internal data). This alteration has been classified as pathogenic by multifactorial analysis (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). Based on an internal structural assessment, this alteration is in the core of the connector domain and is highly destabilizing in an established sensitive region (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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