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
Ambry Genetics RCV000223301 SCV000276729 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence,Well-characterized mutation at same position,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
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 colon cancer 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.

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