ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.595T>C (p.Cys199Arg)
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.595T>C (p.Cys199Arg)
Variation ID: 91146 Accession: VCV000091146.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47410322 (GRCh38) [ NCBI UCSC ] 2: 47637461 (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 Mar 24, 2015 May 1, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.595T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Cys199Arg missense NM_000251.2:c.595T>C NM_001258281.1:c.397T>C NP_001245210.1:p.Cys133Arg missense NC_000002.12:g.47410322T>C NC_000002.11:g.47637461T>C NG_007110.2:g.12199T>C LRG_218:g.12199T>C LRG_218t1:c.595T>C P43246:p.Cys199Arg - Protein change
- C199R, C133R
- Other names
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- Canonical SPDI
- NC_000002.12:47410321:T:C
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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 |
7313 | 7466 |
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) |
reviewed by expert panel
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Sep 5, 2013 | RCV000076650.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 8, 2024 | RCV001854333.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 7, 2023 | RCV003315405.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 14, 2024 | RCV004019518.1 |
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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Pathogenic
(Sep 05, 2013)
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reviewed by expert panel
Method: research
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Lynch Syndrome
Affected status: unknown
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107685.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
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Comment:
Multifactorial likelihood analysis posterior probability >0.99
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Pathogenic
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: yes
Allele origin:
unknown
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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004015213.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
The p.C199R variant (also known as c.595T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide … (more)
The p.C199R variant (also known as c.595T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 595. The cysteine at codon 199 is replaced by arginine, an amino acid with highly dissimilar properties. Two other alterations at the same amino acid position, p.C199Y and p.C199W, have been reported as likely pathogenic. This variant was not reported in populationbased cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In-silico prediction show pathogenic computational verdict based on 12 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI and SIFT vs no benign predictions. Therefore, this variant has been classified as pathogenic. (less)
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Pathogenic
(Jan 08, 2024)
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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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Invitae
Accession: SCV002269120.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 199 of the MSH2 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 199 of the MSH2 protein (p.Cys199Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 9777949, 12386821, 18561205). ClinVar contains an entry for this variant (Variation ID: 91146). 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%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17720936, 28422960, 29731845, 30998989, 31237724). This variant disrupts the p,Cys199 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17440950). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 14, 2024)
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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: SCV005033626.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The p.C199R pathogenic mutation (also known as c.595T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at … (more)
The p.C199R pathogenic mutation (also known as c.595T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 595. The cysteine at codon 199 is replaced by arginine, an amino acid with highly dissimilar properties. In one study, this alteration was detected in an individual diagnosed with rectal cancer at 28 years of age and a glioblastoma at 37 and whose tumor demonstrated high microsatellite instability and absent staining of MSH2 by immunohistochemistry (IHC). In addition, this individual had a reported family history significant for 2 sisters diagnosed with colorectal cancer, one of which underwent testing and was also found to have the p.C199R alteration (Leung SY et al. Am J Pathol. 1998;153(4):1181-8; Chan TL et al. J. Natl. Cancer Inst., 1999 Jul;91:1221-6). In a separate study, functional assays in yeast demonstrated that the p.C199R (p.C195R in yeast) alteration resulted in a reduction of MSH2 levels to 2% of wild-type, inhibited mismatch repair activity, and destabilized protein subunit interactions. Based on the 3D protein structures provided in this publication, codon 199 (195 in yeast) is crucial for proper interaction between domains 1 and 2 in the inner core (Gammie AE et al. Genetics. 2007;177(2):707-21). Another functional study demonstrated that C199R has reduced nuclear localization compared to the wild type (Nielsen SV et al. PLoS Genet., 2017 Apr;13:e1006739). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). 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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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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Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
Functional interrogation of Lynch syndrome-associated MSH2 missense variants via CRISPR-Cas9 gene editing in human embryonic stem cells. | Rath A | Human mutation | 2019 | PMID: 31237724 |
Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome. | Bouvet D | Gastroenterology | 2019 | PMID: 30998989 |
Analysis of human MutS homolog 2 missense mutations in patients with colorectal cancer. | Zhang X | Oncology letters | 2018 | PMID: 29731845 |
Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations. | Nielsen SV | PLoS genetics | 2017 | PMID: 28422960 |
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. | Thompson BA | Nature genetics | 2014 | PMID: 24362816 |
Missense mutations of MLH1 and MSH2 genes detected in patients with gastrointestinal cancer are associated with exonic splicing enhancers and silencers. | Zhu M | Oncology letters | 2013 | PMID: 23760103 |
Functional analysis of human mismatch repair gene mutations identifies weak alleles and polymorphisms capable of polygenic interactions. | Martinez SL | Proceedings of the National Academy of Sciences of the United States of America | 2010 | PMID: 20176959 |
Anaplastic oligoastrocytoma in Turcot syndrome. | Baehring J | Journal of neuro-oncology | 2009 | PMID: 19495563 |
A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. | Tournier I | Human mutation | 2008 | PMID: 18561205 |
Functional characterization of pathogenic human MSH2 missense mutations in Saccharomyces cerevisiae. | Gammie AE | Genetics | 2007 | PMID: 17720936 |
Immunohistochemical staining for mismatch repair proteins, and its relevance in the diagnosis of hereditary non-polyposis colorectal cancer. | Ewald J | The British journal of surgery | 2007 | PMID: 17440950 |
Germline mutations of the hMLH1 and hMSH2 mismatch repair genes in Belgian hereditary nonpolyposis colon cancer (HNPCC) patients. | Spaepen M | Familial cancer | 2006 | PMID: 16736289 |
Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers. | Yuen ST | Oncogene | 2002 | PMID: 12386821 |
Frequent microsatellite instability and mismatch repair gene mutations in young Chinese patients with colorectal cancer. | Chan TL | Journal of the National Cancer Institute | 1999 | PMID: 10413423 |
Microsatellite instability and mutation of DNA mismatch repair genes in gliomas. | Leung SY | The American journal of pathology | 1998 | PMID: 9777949 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.595T%3EC | - | - | - | - |
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Text-mined citations for rs63751110 ...
HelpRecord last updated May 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.