ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.2030C>G (p.Thr677Arg)
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.
Pathogenic(3); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.2030C>G (p.Thr677Arg)
Variation ID: 233888 Accession: VCV000233888.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47476391 (GRCh38) [ NCBI UCSC ] 2: 47703530 (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 Apr 29, 2017 Sep 29, 2024 Aug 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.2030C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Thr677Arg missense NM_001258281.1:c.1832C>G NP_001245210.1:p.Thr611Arg missense NC_000002.12:g.47476391C>G NC_000002.11:g.47703530C>G NG_007110.2:g.78268C>G LRG_218:g.78268C>G LRG_218t1:c.2030C>G LRG_218p1:p.Thr677Arg - Protein change
- T677R, T611R
- Other names
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- Canonical SPDI
- NC_000002.12:47476390:C:G
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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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 15, 2021 | RCV000215510.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 30, 2023 | RCV000462315.7 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 9, 2024 | RCV000484436.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 7, 2023 | RCV003454658.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Uncertain significance
(Jul 11, 2019)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001354849.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This missense variant replaces threonine with arginine at codon 677 of the MSH2 protein. Computational prediction tools and conservation analyses suggest that this variant may … (more)
This missense variant replaces threonine with arginine at codon 677 of the MSH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been observed in individuals affected with rectal cancer (PMID: 22086678, 27432916). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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. (less)
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Pathogenic
(Dec 30, 2023)
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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: SCV000548317.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 677 of the MSH2 protein (p.Thr677Arg). … (more)
This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 677 of the MSH2 protein (p.Thr677Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 22086678, 27432916; Invitae). ClinVar contains an entry for this variant (Variation ID: 233888). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 15, 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: SCV000278353.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.T677R pathogenic mutation (also known as c.2030C>G), located in coding exon 13 of the MSH2 gene, results from a C to G substitution at … (more)
The p.T677R pathogenic mutation (also known as c.2030C>G), located in coding exon 13 of the MSH2 gene, results from a C to G substitution at nucleotide position 2030. The threonine at codon 677 is replaced by arginine, an amino acid with similar properties. This variant has been identified in probands whose colorectal tumors demonstrated high microsatellite instability (MSI-H) and isolated loss of MSH6 expression by immunohistochemistry (IHC) was also seen in one of the tumors (Ambry internal data). This variant was reported in an individual diagnosed with mismatch repair-deficient rectal cancer at age 45 whose personal and family history met Bethesda guidelines, but not Amsterdam I or II criteria (de Rosa N et al. J. Clin. Oncol., 2016 Sep;34:3039-46). This variant was also reported in a 48 year old individual with MSI-H rectal cancer that demonstrated intact mismatch repair protein expression by IHC and had no family history of a Lynch syndrome–associated cancers (Bartley AN et al. Cancer Prev Res (Phila), 2012 Feb;5:320-7). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). The yeast equivalent of this variant also demonstrated increased mutation rates in a multiplexed functional assay performed using Saccharomyces cerevisiae (Ollodart AR et al. Genetics, 2021 Jun;218:). Based on internal structural analysis, p.T677R introduces a large, charged side-chain into the ATP-binding pocket of MSH2, a region sensitive to alteration (Ambry internal data; Antony E et al. DNA Repair (Amst), 2006 Feb;5:153-62; Warren JJ et al. Mol Cell, 2007 May;26:579-92). 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
(Aug 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000569536.6
First in ClinVar: Apr 29, 2017 Last updated: Sep 29, 2024 |
Comment:
Observed in an individual with early-onset rectal cancer whose tumor displayed mismatch repair deficiency on immunohistochemistry and another individual with rectal cancer whose tumor demonstrated … (more)
Observed in an individual with early-onset rectal cancer whose tumor displayed mismatch repair deficiency on immunohistochemistry and another individual with rectal cancer whose tumor demonstrated microsatellite instability (MSI-H) and normal protein expression on immunohistochemistry (PMID: 27432916, 22086678); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27432916, 22086678, 22208277, 28765196, 16214425, 17531815, 30787465, 33848333, 36550560, 33357406, 18822302, 21120944) (less)
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Likely pathogenic
(Aug 07, 2023)
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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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Myriad Genetics, Inc.
Accession: SCV004186741.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33357406]. This variant is expected to disrupt protein structure [Myriad … (more)
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33357406]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Pathogenic
(May 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004220971.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The MSH2 c.2030C>G (p.Thr677Arg) variant has been reported in the published literature in individuals with rectal cancer (PMID: 22086678 (2012), 27432916 (2016)). Published functional studies … (more)
The MSH2 c.2030C>G (p.Thr677Arg) variant has been reported in the published literature in individuals with rectal cancer (PMID: 22086678 (2012), 27432916 (2016)). Published functional studies show that this variant is damaging to protein function (PMID: 33357406 (2021), 33848333 (2021)).This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. (less)
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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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Multiplexing mutation rate assessment: determining pathogenicity of Msh2 variants in Saccharomyces cerevisiae. | Ollodart AR | Genetics | 2021 | PMID: 33848333 |
Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
DNA Mismatch Repair Deficiency in Rectal Cancer: Benchmarking Its Impact on Prognosis, Neoadjuvant Response Prediction, and Clinical Cancer Genetics. | de Rosa N | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 27432916 |
Identification of cancer patients with Lynch syndrome: clinically significant discordances and problems in tissue-based mismatch repair testing. | Bartley AN | Cancer prevention research (Philadelphia, Pa.) | 2012 | PMID: 22086678 |
Structure of the human MutSalpha DNA lesion recognition complex. | Warren JJ | Molecular cell | 2007 | PMID: 17531815 |
Contribution of Msh2 and Msh6 subunits to the asymmetric ATPase and DNA mismatch binding activities of Saccharomyces cerevisiae Msh2-Msh6 mismatch repair protein. | Antony E | DNA repair | 2006 | PMID: 16214425 |
Text-mined citations for rs876660711 ...
HelpRecord last updated Oct 08, 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.