ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.715C>T (p.Gln239Ter)
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.715C>T (p.Gln239Ter)
Variation ID: 91185 Accession: VCV000091185.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47412483 (GRCh38) [ NCBI UCSC ] 2: 47639622 (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.715C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Gln239Ter nonsense NM_001258281.1:c.517C>T NP_001245210.1:p.Gln173Ter nonsense NC_000002.12:g.47412483C>T NC_000002.11:g.47639622C>T NG_007110.2:g.14360C>T LRG_218:g.14360C>T LRG_218t1:c.715C>T LRG_218p1:p.Gln239Ter - Protein change
- Q239*, Q173*
- Other names
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- Canonical SPDI
- NC_000002.12:47412482: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 |
7314 | 7467 |
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 | RCV000076689.4 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 21, 2023 | RCV000410998.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 15, 2021 | RCV000561407.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 15, 2021 | RCV000629942.6 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001358384.1 |
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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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: SCV000107724.3
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
(Dec 30, 2015)
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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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Counsyl
Accession: SCV000488116.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Nov 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: SCV000664857.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.Q239* pathogenic mutation (also known as c.715C>T), located in coding exon 4 of the MSH2 gene, results from a C to T substitution at … (more)
The p.Q239* pathogenic mutation (also known as c.715C>T), located in coding exon 4 of the MSH2 gene, results from a C to T substitution at nucleotide position 715. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This alteration has been reported in individuals with personal and or family history consistent with hereditary non-polyposis colorectal cancer (Kurzawski G et al. Clin. Genet., 2006 Jan;69:40-7; Schofield L et al. Int J Cancer, 2009 Mar;124:1097-102; Skeldon SC et al. Eur. Urol., 2013 Feb;63:379-85; Yamashita K et al. Intern Med, 2021 Sep;60:2719-2724). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
(Jan 31, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary non-polyposis colorectal cancer, type 1
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434862.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
This c.715C>T (p.Gln239*) variant in the MSH2 gene is predicted to produce a premature termination codon and is predicted to lead to nonsense-mediated mRNA decay, … (more)
This c.715C>T (p.Gln239*) variant in the MSH2 gene is predicted to produce a premature termination codon and is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant has been observed in two unrelated individuals affected with Lynch associated tumors (PMID 16451135, 22883484) and is absent from general population databases. Therefore, this c.715C>T (p.Gln239*) variant in the MSH2 gene is classified as pathogenic. (less)
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Pathogenic
(Mar 21, 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: SCV004018337.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 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
(Mar 15, 2021)
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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: SCV000750898.4
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant has … (more)
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12626904, 22883484, 16451135). ClinVar contains an entry for this variant (Variation ID: 91185). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln239*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001554101.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
Please note, this variant was reported in old database in case ….CB4754
Number of individuals with the variant: 1
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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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Interval between the First Cancer and the Genetic Diagnosis in Lynch Syndrome Probands. | Yamashita K | Internal medicine (Tokyo, Japan) | 2021 | PMID: 33746161 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
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 |
A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry. | Thompson BA | Human mutation | 2013 | PMID: 22949379 |
Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. | Skeldon SC | European urology | 2013 | PMID: 22883484 |
Population-based detection of Lynch syndrome in young colorectal cancer patients using microsatellite instability as the initial test. | Schofield L | International journal of cancer | 2009 | PMID: 19072991 |
Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study). | Kurzawski G | Clinical genetics | 2006 | PMID: 16451135 |
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 |
Early-age-at-onset colorectal cancer and microsatellite instability as markers of hereditary nonpolyposis colorectal cancer. | Pucciarelli S | Diseases of the colon and rectum | 2003 | PMID: 12626904 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.715C%3ET | - | - | - | - |
Text-mined citations for rs63750488 ...
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.