ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.2074G>T (p.Gly692Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.2074G>T (p.Gly692Trp)
Variation ID: 428464 Accession: VCV000428464.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47476435 (GRCh38) [ NCBI UCSC ] 2: 47703574 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 26, 2017 Jun 17, 2024 Mar 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.2074G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Gly692Trp missense NM_001258281.1:c.1876G>T NP_001245210.1:p.Gly626Trp missense NC_000002.12:g.47476435G>T NC_000002.11:g.47703574G>T NG_007110.2:g.78312G>T LRG_218:g.78312G>T LRG_218t1:c.2074G>T LRG_218p1:p.Gly692Trp - Protein change
- G692W, G626W
- Other names
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- Canonical SPDI
- NC_000002.12:47476434:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7401 | 7563 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Jul 22, 2021 | RCV000490880.4 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Mar 7, 2024 | RCV000659883.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 1, 2018 | RCV000664310.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 20, 2020 | RCV001209603.8 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(May 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: yes
Allele origin:
somatic
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000788242.2
First in ClinVar: Jul 28, 2018 Last updated: Mar 10, 2019 |
Comment:
MSH2 NM_000251.2:c.2074G>T has a 96.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated … (more)
MSH2 NM_000251.2:c.2074G>T has a 96.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214. In-silico prediction scores using MAPP and PolyPhen2 give this variant a high likelihood of being pathogenic. This variant has been reported by another laboratory to segregate with Lynch syndrome associated cancers in one family. In addition, a variant at the same position (p.G692R, NM_000179.2:c.2074 G to C) is classified as likely pathogenic (class 4) by the InSiGHT consortium based on case reports and functional analysis. The absence of multiple definitive somatic mutations in MSH2 in tumor is consistent with this variant being pathogenic. Combining all the evidence, this variant is likely pathogenic. (less)
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Pathogenic
(Oct 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001381046.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly692 amino acid residue in MSH2. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly692 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10612836, 12624141, 23454724, 23729658, 28577310, 29212164). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has been observed to segregate with Lynch syndrome in a family (external communication). Also, it has been observed in several individuals affected with clinical features of Lynch syndrome (PMID: 28135145, Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 428464). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with tryptophan at codon 692 of the MSH2 protein (p.Gly692Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. (less)
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Pathogenic
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000580439.6
First in ClinVar: Jun 25, 2017 Last updated: May 01, 2024 |
Comment:
The p.G692W pathogenic mutation (also known as c.2074G>T), located in coding exon 13 of the MSH2 gene, results from a G to T substitution at … (more)
The p.G692W pathogenic mutation (also known as c.2074G>T), located in coding exon 13 of the MSH2 gene, results from a G to T substitution at nucleotide position 2074. The glycine at codon 692 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant has been detected as a germline and a somatic mutation in multiple patients with mismatch repair-deficient, MSI-H colorectal cancers (Haraldsdottir S et al. Gastroenterology 2014 Dec;147:1308-1316.e1; Yurgelun MB et al. J Clin Oncol. 2017 Apr 1;35(10):1086-1095; LaDuca H et al. PLoS One. 2017 Feb 2;12(2):e0170843). In addition, using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as likely pathogenic (Shirts BH et al. Am J Hum Genet. 2018 Jul 5;103(1):19-29). Two other alterations at the same codon, p.G692R and p.G692V, have been detected in several Lynch/HNPCC syndrome families with mismatch repair-deficient, MSI-H tumors (Isidro et al. Hum Mut. 2000 Jan; 15(1):116; Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13; Casey G et al. JAMA, 2005 Feb;293:799-809; Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Choi YH et al. Hered Cancer Clin Pract, 2009 Aug;7:14; Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463), and the p.G692R alteration has been shown to have reduced protein expression and impaired function (Gammie et al. Genetics. 2007 Oct; 177(2): 707-21; Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113:4128-33). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Likely pathogenic
(Mar 07, 2024)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005053434.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Uncertain significance
(Nov 01, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Older and outlier claim with insufficient supporting evidence
Source: ClinGen
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Lynch syndrome 1
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781775.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort. | Raskin L | Oncotarget | 2017 | PMID: 29212164 |
Elucidating the molecular basis of MSH2-deficient tumors by combined germline and somatic analysis. | Vargas-Parra GM | International journal of cancer | 2017 | PMID: 28577310 |
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. | Haraldsdottir S | Gastroenterology | 2014 | PMID: 25194673 |
UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families. | Grandval P | Database : the journal of biological databases and curation | 2013 | PMID: 23729658 |
Colorectal cancer in a 9-year-old due to combined EPCAM and MSH2 germline mutations: case report of a unique genotype and immunophenotype. | Li-Chang HH | Journal of clinical pathology | 2013 | PMID: 23454724 |
Functional characterization of pathogenic human MSH2 missense mutations in Saccharomyces cerevisiae. | Gammie AE | Genetics | 2007 | PMID: 17720936 |
Cancer risk in 348 French MSH2 or MLH1 gene carriers. | Parc Y | Journal of medical genetics | 2003 | PMID: 12624141 |
Four novel MSH2 / MLH1 gene mutations in portuguese HNPCC families. | Isidro G | Human mutation | 2000 | PMID: 10612836 |
Text-mined citations for rs63750232 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.