Submissions for variant NM_000251.3(MSH2):c.2048G>T (p.Gly683Val)

gnomAD frequency: 0.00001  dbSNP: rs755920849

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000199994	SCV000254399	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 683 of the MSH2 protein (p.Gly683Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and/or colon cancer (PMID: 11606497, 34282249). ClinVar contains an entry for this variant (Variation ID: 216348). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 95%. This variant disrupts the p.Gly683Arg amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11606497, 18931482, 19731080, 23690608, 26248088). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Counsyl	RCV000410314	SCV000487818	uncertain significance	Lynch syndrome 1	2015-11-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000767061	SCV000565927	uncertain significance	not provided	2023-08-22	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a neutral effect: restored mismatch repair (MMR) function in a MSH2 knockout cell line (Jia et al., 2020); This variant is associated with the following publications: (PMID: 28503720, 18822302, 21120944, 34282249, 25085752, 33357406, 11606497)
Ambry Genetics	RCV000490871	SCV000580585	likely benign	Hereditary cancer-predisposing syndrome	2022-11-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485278	SCV000601452	uncertain significance	not specified	2017-04-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Color Diagnostics, LLC DBA Color Health	RCV000490871	SCV001344909	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 683 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with colon cancer (PMID: 11606497) and in individuals from a family affected with breast cancer (PMID: 34282249). This variant has been identified in 2/251470 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.2047G>A (p.Gly683Arg), is considered to be disease-causing (ClinVar variation ID: 90868), suggesting that this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Division of Medical Genetics, University of Washington	RCV000410314	SCV001434268	uncertain significance	Lynch syndrome 1	2019-12-21	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in an individual with colon cancer and an individual with breast cancer who also had a pathogenic BRCA1 variant (Samowitz 2001, Rummel 2017). This variant has an overall allele frequency of 0.000008 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PM2; PP3
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000410314	SCV001737440	uncertain significance	Lynch syndrome 1	2021-02-25	criteria provided, single submitter	clinical testing	The MSH2 c.2048G>T (p.Gly683Val) missense change has a maximum subpopulation frequency of 0.001758% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/2-47703548-G-T?dataset=gnomad_r2_1). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been observed in an individual with late-onset colorectal cancer whose tumor demonstrated microsatellite instability (PMID: 11606497). Of note, this individual reportedly did not have any first degree relatives with cancer. This variant has also been observed in an individual with a cancer that is not part of the Lynch syndrome tumor spectrum and did not demonstrate microsatellite instability (internal data). A different missense substitution at this codon (p.Gly683Arg) has been determined to be pathogenic (PMID: 18931482, 11606497, 19731080, 26248088, 23690608). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, PP3.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000767061	SCV002009338	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000485278	SCV002065338	uncertain significance	not specified	2021-06-15	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.2048G>T, in exon 13 that results in an amino acid change, p.Gly683Val. This sequence change has been reported in one individual with a history of microsatellite unstable colorectal cancer (PMID: 11606497). This sequence change has been reported in the gnomAD database with a frequency of 0.0018% in the European (non-Finnish) subpopulation(dbSNP rs755920849). The p.Gly683Val change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Gly683Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). A different missense variant at this same position (p.Gly683Arg) has been reported as pathogenic for Lynch syndrome (31615790, 24362816, 11606497, 18931482, 19731080, 26248088). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly683Val change remains unknown at this time.
Myriad Genetics, Inc.	RCV000410314	SCV004018256	likely benign	Lynch syndrome 1	2023-03-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
All of Us Research Program, National Institutes of Health	RCV003997017	SCV004825250	uncertain significance	Lynch syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 683 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with colon cancer (PMID: 11606497) and in individuals from a family affected with breast cancer (PMID: 34282249). This variant has been identified in 2/251470 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.2047G>A (p.Gly683Arg), is considered to be disease-causing (ClinVar variation ID: 90868), suggesting that this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.