ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.118G>A (p.Gly40Ser) (rs63751260)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491838 SCV000580530 likely benign Hereditary cancer-predisposing syndrome 2016-08-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with mutation in same gene (phase unknown)
Color RCV000491838 SCV000684914 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-18 criteria provided, single submitter clinical testing
GeneDx RCV000236371 SCV000293503 uncertain significance not provided 2015-12-02 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.118G>A at the cDNA level, p.Gly40Ser (G40S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). MSH2 Gly40Ser was reported as a germline observation in 1 of 180 Japanese patients with sporadic colorectal cancer and absent in 122 healthy Japanese controls (Yamada 2003). This variant has also been reported in an individual with metachronous colon cancers meeting Amsterdam II criteria for Lynch syndrome found to have a colon tumor with microsatellite instability and absent MSH2 staining (Kochi 2015). MSH2 Gly40Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Gly40Ser occurs at a position that is conserved in mammals and is located within the mismatch binding domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Gly40Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781559 SCV000919699 uncertain significance not specified 2018-11-19 criteria provided, single submitter clinical testing Variant summary: MSH2 c.118G>A (p.Gly40Ser) results in a non-conservative amino acid change located in the N-terminal DNA mismatch repair protein MutS-like domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 222780 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.118G>A has been reported in the literature in individuals affected with Lynch Syndrome (Yamada_2010, Kochi_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance (3x) and once as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076056 SCV000107069 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000627704 SCV000284097 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 40 of the MSH2 protein (p.Gly40Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs63751260, ExAC 0.02%). This variant has been reported in individuals affected with colorectal cancer (PMID: 12792735, 26380806). ClinVar contains an entry for this variant (Variation ID: 90560). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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