ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.862C>T (p.Gln288Ter)
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.862C>T (p.Gln288Ter)
Variation ID: 91233 Accession: VCV000091233.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47414338 (GRCh38) [ NCBI UCSC ] 2: 47641477 (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.862C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Gln288Ter nonsense NM_001258281.1:c.664C>T NP_001245210.1:p.Gln222Ter nonsense NC_000002.12:g.47414338C>T NC_000002.11:g.47641477C>T NG_007110.2:g.16215C>T LRG_218:g.16215C>T LRG_218t1:c.862C>T LRG_218p1:p.Gln288Ter - Protein change
- Q288*, Q222*
- Other names
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- Canonical SPDI
- NC_000002.12:47414337:C: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 |
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
Help
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 | RCV000076738.4 | |
Pathogenic (3) |
criteria provided, single submitter
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Jun 9, 2017 | RCV000484173.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 12, 2022 | RCV000528830.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2022 | RCV001183048.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 28, 2023 | RCV003452970.1 |
Submissions - Germline
Classification
Help
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: SCV000107775.3
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:
Coding sequence variation resulting in a stop codon
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Pathogenic
(Jun 09, 2017)
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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: SCV000565185.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
This variant is denoted MSH2 c.862C>T at the cDNA level and p.Gln288Ter (Q288X) at the protein level. The substitution creates a nonsense variant, which changes … (more)
This variant is denoted MSH2 c.862C>T at the cDNA level and p.Gln288Ter (Q288X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been identified in multiple families with Hereditary Nonpolyposis Colorectal Cancer and in at least 1 individual with Muir-Torre Syndrome, and tumor studies from some of these individuals showed microsatellite instability and loss of MSH2 protein expression (Wijnen 1995, Wijnen 1997, Kruse 1998, Pistorius 2000, Hendriks 2003, Lage 2004, Mangold 2004, Mangold 2005, Overbeek 2007, Dominquez-Valentin 2013). Based on current information, we consider this variant to be pathogenic. (less)
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Pathogenic
(Apr 12, 2022)
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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: SCV000625475.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91233). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91233). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 7726159, 12547705, 15235030, 15849733, 28874130). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln288*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). (less)
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Pathogenic
(Jul 28, 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: SCV004186899.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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Pathogenic
(Jan 03, 2022)
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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: SCV001348703.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 5 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 5 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 7726159, 12547705, 15235030, 15849733, 24344984). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Mar 27, 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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Ambry Genetics
Accession: SCV002682471.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.Q288* pathogenic mutation (also known as c.862C>T), located in coding exon 5 of the MSH2 gene, results from a C to T substitution at … (more)
The p.Q288* pathogenic mutation (also known as c.862C>T), located in coding exon 5 of the MSH2 gene, results from a C to T substitution at nucleotide position 862. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This mutation has been identified in multiple HNPCC/Lynch syndrome families of various ethnicities, including patients whose tumors were MSI-H and demonstrated loss of MSH2 protein expression by IHC (Wijnen J et al. Am. J. Hum. Genet. 1997 Aug;61:329-35; Pistorius SR et al. Int. J Colorectal Dis, 2000 Nov;15:255-63; Hendriks Y et al. Am. J. Pathol. 2003 Feb;162:469-77; Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702; Rossi BM et al. BMC Cancer 2017 Sep;17:623). This mutation has also been reported in an individual with Muir-Torre phenotype who had colon cancer and multiple sebaceous skin tumors, one of which was shown to be MSI-H and demonstrated loss of MSH2 staining by IHC analysis (Kruse R et al. Am. J. Hum. Genet. 1998 Jul;63(1):63-70; Mangold E et al. J. Med. Genet., 2004 Jul;41:567-72). Of note, this alteration is also designated as p.Gln288*, p.Gln288X, "C to T at 862 (Gln to Stop)," Q288X, and "862CAG>TAG," in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956871.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966792.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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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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A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. | Rossi BM | BMC cancer | 2017 | PMID: 28874130 |
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 |
Mutation spectrum in South American Lynch syndrome families. | Dominguez-Valentin M | Hereditary cancer in clinical practice | 2013 | PMID: 24344984 |
Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. | Mangold E | International journal of cancer | 2005 | PMID: 15849733 |
A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome. | Mangold E | Journal of medical genetics | 2004 | PMID: 15235030 |
Conventional and tissue microarray immunohistochemical expression analysis of mismatch repair in hereditary colorectal tumors. | Hendriks Y | The American journal of pathology | 2003 | PMID: 12547705 |
Clinical consequences of molecular diagnosis in families with mismatch repair gene germline mutations. | Pistorius SR | International journal of colorectal disease | 2000 | PMID: 11151427 |
Muir-Torre phenotype has a frequency of DNA mismatch-repair-gene mutations similar to that in hereditary nonpolyposis colorectal cancer families defined by the Amsterdam criteria. | Kruse R | American journal of human genetics | 1998 | PMID: 9634524 |
Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations. | Wijnen J | American journal of human genetics | 1997 | PMID: 9311737 |
Seven new mutations in hMSH2, an HNPCC gene, identified by denaturing gradient-gel electrophoresis. | Wijnen J | American journal of human genetics | 1995 | PMID: 7726159 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.862C%3ET | - | - | - | - |
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Text-mined citations for rs63750097 ...
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.