ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2048G>T (p.Gly683Val) (rs755920849)

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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 RCV000490871 SCV000580585 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,Insufficient or conflicting evidence
Counsyl RCV000410314 SCV000487818 uncertain significance Lynch syndrome I 2015-11-17 criteria provided, single submitter clinical testing
GeneDx RCV000767061 SCV000565927 uncertain significance not provided 2017-03-13 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2048G>T at the cDNA level, p.Gly683Val (G683V) at the protein level, and results in the change of a Glycine to a Valine (GGG>GTG). This variant was observed in at least one individual with late-onset colon cancer whose tumor demonstrated microsatellite instability (Samowitz 2001). Of note, this individual reportedly did not have any first degree relatives with cancer. MSH2 Gly683Val was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Gly683Val occurs at a position that is conserved across species and is located within the ATPase domain (Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Gly683Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000485278 SCV000917724 uncertain significance not specified 2018-12-14 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2048G>T (p.Gly683Val) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal 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 8.1e-06 in 246250 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2048G>T has been reported in the literature in individuals affected with colon cancer and breast cancer, the latter of which carried a pathogenic BRCA1 variant (Samowitz_2001, Rummel_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000199994 SCV000254399 uncertain significance Hereditary nonpolyposis colon cancer 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 683 of the MSH2 protein (p.Gly683Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with colon cancer (PMID: 11606497). ClinVar contains an entry for this variant (Variation ID: 216348). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Gly683Arg) has been determined to be pathogenic (PMID: 18931482, 11606497, 19731080, 26248088, 23690608). 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 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485278 SCV000601452 uncertain significance not specified 2017-04-11 criteria provided, single submitter clinical testing

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