ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.1661+1G>C
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.1661+1G>C
Variation ID: 956575 Accession: VCV000956575.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47466809 (GRCh38) [ NCBI UCSC ] 2: 47693948 (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 Jul 16, 2020 May 1, 2024 Aug 3, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000002.12:47466808:G: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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- Links
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 |
7395 | 7557 |
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) |
criteria provided, single submitter
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Jun 27, 2023 | RCV001229406.7 | |
Pathogenic (1) |
criteria provided, single submitter
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May 23, 2023 | RCV003294097.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 3, 2023 | RCV003449722.1 |
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
(Aug 03, 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: SCV004188131.1
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: 18561205]. (less)
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Pathogenic
(Jun 27, 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: SCV001401851.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic … (more)
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and exon 10 skipping and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 956575). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 12624141, 16034045, 16142001, 17569143, 21642682). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 10 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. (less)
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Pathogenic
(May 23, 2023)
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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: SCV004002480.2
First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024 |
Comment:
The c.1661+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 10 of the MSH2 gene. This variant was … (more)
The c.1661+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 10 of the MSH2 gene. This variant was identified in a proband whose colon cancer demonstrated loss of MSH2 and MSH6 protein expression by immunohistochemistry (IHC) (Ambry internal data). This variant was also reported in a proband with a family history of urinary tract cancer (Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 Jan;29:193-199). Another alteration impacting the same donor site (c.1661+1G>T) has been detected in several individuals whose colorectal or endometrial cancers demonstrated loss of MSH2 and MSH6 protein expression on IHC (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. 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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Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome. | Wischhusen JW | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2020 | PMID: 31615790 |
Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. | Bonadona V | JAMA | 2011 | PMID: 21642682 |
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 |
Germline MLH1 and MSH2 mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: implications for genetic testing. | Papp J | World journal of gastroenterology | 2007 | PMID: 17569143 |
Value of microsatellite instability typing in detecting hereditary non-polyposis colorectal cancer. A prospective multicentric study by the Association Aquitaine Gastro. | Bécouarn Y | Gastroenterologie clinique et biologique | 2005 | PMID: 16142001 |
Immunohistochemistry identifies carriers of mismatch repair gene defects causing hereditary nonpolyposis colorectal cancer. | Stormorken AT | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2005 | PMID: 16034045 |
Cancer risk in 348 French MSH2 or MLH1 gene carriers. | Parc Y | Journal of medical genetics | 2003 | PMID: 12624141 |
Text-mined citations for rs267607969 ...
HelpRecord last updated Jun 10, 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.