ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.2647del (p.Ile883fs)
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.2647del (p.Ile883fs)
Variation ID: 91030 Accession: VCV000091030.17
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 2p21 2: 47482786 (GRCh38) [ NCBI UCSC ] 2: 47709925 (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 Aug 21, 2017 Feb 20, 2024 Jun 13, 2018 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.2647del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Ile883fs frameshift NM_000251.1:c.2647delA NM_000251.2:c.2647delA NM_001258281.1:c.2449del NP_001245210.1:p.Ile817fs frameshift NC_000002.12:g.47482791del NC_000002.11:g.47709930del NG_007110.2:g.84668del LRG_218:g.84668del - Protein change
- I817fs
- Other names
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- Canonical SPDI
- NC_000002.12:47482785:AAAAAA:AAAAA
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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 |
7262 | 7411 |
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 (2) |
reviewed by expert panel
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Jun 13, 2018 | RCV000076532.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2022 | RCV000160633.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 5, 2024 | RCV000537212.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 23, 2020 | RCV000497287.2 |
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
(Jun 13, 2018)
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reviewed by expert panel
Method: curation
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Lynch syndrome 1
Affected status: yes
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107561.5
First in ClinVar: Dec 19, 2013 Last updated: Dec 11, 2022 |
Comment:
This variant is before the cutoff (codon 888) and therefore Class 5
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Pathogenic
(Jan 24, 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: SCV000580441.5
First in ClinVar: Jun 24, 2017 Last updated: Nov 29, 2022 |
Comment:
The c.2647delA pathogenic mutation, located in coding exon 16 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 2647, causing … (more)
The c.2647delA pathogenic mutation, located in coding exon 16 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 2647, causing a translational frameshift with a predicted alternate stop codon (p.I883Lfs*9). This alteration occurs at the 3' terminus of theMSH2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 52 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This mutation has been reported in multiple individuals and families with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Percesepe A et al. J. Clin. Oncol., 2001 Oct;19:3944-50; Bozzao C et al. Cancer, 2011 Sep;117:4325-35; Susswein LR et al. Genet Med, 2016 08;18:823-32; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Roberts ME et al. Genet Med, 2018 10;20:1167-1174). This variant has been identified in probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability and/or loss of MSH6 but retained MSH2 expression by immunohistochemistry (Hampel H et al. N Engl J Med, 2005 May;352:1851-60; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Apr 23, 2020)
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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: SCV000211234.4
First in ClinVar: Feb 24, 2015 Last updated: Aug 21, 2017 |
Comment:
Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population … (more)
Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with MSH2-related cancers (Percesepe 2001, Bozzao 2011, Susswein 2016); This variant is associated with the following publications: (PMID: 30322717, 11579115, 29025352, 21387278, 26681312, 14970868) (less)
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Pathogenic
(Jan 15, 2020)
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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: SCV001359868.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This variant deletes 1 nucleotide in exon 16 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide in exon 16 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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
(Jan 05, 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: SCV000625400.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ile883Leufs*9) in the MSH2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Ile883Leufs*9) in the MSH2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acid(s) of the MSH2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 11579115, 14970868, 30322717). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91030). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Ile883 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9774676, 17531815, 18822302). 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
(Aug 09, 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: SCV004188161.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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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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Germline pathogenic variants identified in women with ovarian tumors. | Carter NJ | Gynecologic oncology | 2018 | PMID: 30322717 |
MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. | Roberts ME | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29345684 |
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
Analysis of telomere dynamics in peripheral blood cells from patients with Lynch syndrome. | Bozzao C | Cancer | 2011 | PMID: 21387278 |
Functional analysis of HNPCC-related missense mutations in MSH2. | Lützen A | Mutation research | 2008 | PMID: 18822302 |
Structure of the human MutSalpha DNA lesion recognition complex. | Warren JJ | Molecular cell | 2007 | PMID: 17531815 |
Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). | Hampel H | The New England journal of medicine | 2005 | PMID: 15872200 |
Genetic testing among high-risk individuals in families with hereditary nonpolyposis colorectal cancer. | Ponz de Leon M | British journal of cancer | 2004 | PMID: 14970868 |
Molecular screening for hereditary nonpolyposis colorectal cancer: a prospective, population-based study. | Percesepe A | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2001 | PMID: 11579115 |
Interactions of human hMSH2 with hMSH3 and hMSH2 with hMSH6: examination of mutations found in hereditary nonpolyposis colorectal cancer. | Guerrette S | Molecular and cellular biology | 1998 | PMID: 9774676 |
http://www.insight-database.org/classifications/?gene=MSH2&variant=c.2647del | - | - | - | - |
http://www.insight-database.org/classifications/?gene=MSH2&variant=c.2647delA | - | - | - | - |
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Text-mined citations for rs63750084 ...
HelpRecord last updated Feb 28, 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.