ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.792+1G>A
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.792+1G>A
Variation ID: 91205 Accession: VCV000091205.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47412561 (GRCh38) [ NCBI UCSC ] 2: 47639700 (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
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000002.12:47412560:G:A
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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 | RCV000076709.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 1, 2022 | RCV001026957.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 5, 2023 | RCV001233639.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2021 | RCV001588899.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 28, 2023 | RCV003452966.1 |
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: SCV000107745.3
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:
Variant causes splicing aberration interrupting known functional domains (full inactivation of variant allele)
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Likely pathogenic
(Jan 04, 2021)
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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: SCV001822507.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Canonical splice site variant predicted to result in an in-frame deletion of the critical connector domains (Lutzen 2008, Kansikas 2011); Not observed in large population … (more)
Canonical splice site variant predicted to result in an in-frame deletion of the critical connector domains (Lutzen 2008, Kansikas 2011); Not observed in large population cohorts (Lek 2016); Reported in individuals with colon cancer with concordant mismatch repair immunohistochemistry results reported to result in skipping of exon 4 (Cunningham 2001, Casey 2005, Rosty 2014).; This variant is associated with the following publications: (PMID: 32390703, 11524701, 23752102, 25117503, 15713769, 25525159) (less)
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Pathogenic
(Oct 24, 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: SCV001354533.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This variant (also known as IVS4+1G>A) causes a G>A nucleotide substitution at the +1 position of intron 4 of the MSH2 gene. Functional RNA studies … (more)
This variant (also known as IVS4+1G>A) causes a G>A nucleotide substitution at the +1 position of intron 4 of the MSH2 gene. Functional RNA studies have shown that this variant causes exon 4 skipping resulting in loss of DNA binding domain (PMID: 15713769). This variant has been reported in individuals affected with colorectal cancer and Lynch syndrome (PMID: 11524701, 15713769, 23752102, 25117503). 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. Based on the available evidence, this variant is classified as Pathogenic. (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: SCV004188014.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an … (more)
This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15713769]. (less)
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Pathogenic
(Dec 05, 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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Invitae
Accession: SCV001406243.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 4 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 4 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with colorectal cancer (PMID: 15713769, 25117503). ClinVar contains an entry for this variant (Variation ID: 91205). Studies have shown that disruption of this splice site results in partial intron inclusion due to the activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 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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Ambry Genetics
Accession: SCV001189437.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The c.792+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the MSH2 gene. This variant has … (more)
The c.792+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the MSH2 gene. This variant has been identified in individuals meeting Amsterdam criteria with microsatellite unstable tumors also demonstrating loss of MSH2 and MSH6 protein expression by immunohistochemistry analysis (Cunningham JM et al. Am. J. Hum. Genet. 2001 Oct;69:780-90; Casey G et al. JAMA, 2005 Feb;293:799-809; Rosty C et al. Fam. Cancer 2014 Dec;13:573-82; Ambry internal data). The colon tumor of one of these patients was also found to have a somatic MSH2 mutation ("1165C>T, R389 stop") (Cunningham JM et al. Am. J. Hum. Genet. 2001 Oct;69:780-90). Additionally, conversion analysis confirmed that the c.792+1G>A variant results in coding exon 4 skipping (Casey G et al. JAMA 2005 Feb;293:799-809). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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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High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. | Rosty C | Familial cancer | 2014 | PMID: 25117503 |
Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. | Casey G | JAMA | 2005 | PMID: 15713769 |
The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. | Cunningham JM | American journal of human genetics | 2001 | PMID: 11524701 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.792%2B1G%3EA | - | - | - | - |
Text-mined citations for rs267607934 ...
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.