ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.34dup (p.Glu12fs)
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.34dup (p.Glu12fs)
Variation ID: 91068 Accession: VCV000091068.21
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 2p21 2: 47403223-47403224 (GRCh38) [ NCBI UCSC ] 2: 47630362-47630363 (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 Feb 20, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.34dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Glu12fs frameshift NM_000251.1:c.34dupG NM_000251.2:c.34dupG NM_001258281.1:c.-31+50dup intron variant NC_000002.12:g.47403225dup NC_000002.11:g.47630364dup NG_007110.2:g.5102dup LRG_218:g.5102dup LRG_218t1:c.34dup LRG_218p1:p.Glu12fs - Protein change
- E12fs
- Other names
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- Canonical SPDI
- NC_000002.12:47403223:GG:GGG
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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 |
7207 | 7355 |
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 | RCV000076570.3 | |
Pathogenic (2) |
criteria provided, single submitter
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Sep 17, 2019 | RCV000202253.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 14, 2022 | RCV000221149.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 6, 2023 | RCV000554624.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 26, 2023 | RCV003452934.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 27, 2022 | RCV002298463.1 |
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: SCV000107601.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comment:
Coding sequence variation resulting in a stop codon
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Pathogenic
(Sep 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002598590.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: MSH2 c.34dupG (p.Glu12GlyfsX70) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: MSH2 c.34dupG (p.Glu12GlyfsX70) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 223170 control chromosomes. c.34dupG has been reported in the literature in individuals affected with Lynch Syndrome. These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 14, 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: SCV000276142.7
First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022 |
Comment:
The c.34dupG pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a duplication of G at nucleotide position 34, causing a … (more)
The c.34dupG pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a duplication of G at nucleotide position 34, causing a translational frameshift with a predicted alternate stop codon (p.E12Gfs*70). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with MSH2-related disease (Ambry internal data). In one study, this mutation was detected in 3/36 colorectal cancer families tested (Colombino M et al. Ann. Oncol. 2003 Oct;14:1530-6). This mutation has also been reported in a male with Muir-Torre syndrome; he had multiple (>30) sebaceous adenomas and sebaceous carcinomas and family history of colon cancer in his father, brother, paternal uncles, and cousin (Landis MN et al. J. Am. Acad. Dermatol. 2011 Nov;65:1054-1058.e1). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as "c.34_35insG" 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)
Number of individuals with the variant: 1
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Pathogenic
(May 18, 2021)
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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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Baylor Genetics
Accession: SCV004196938.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001470550.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
Comment:
This frameshift variant causes the premature termination of MSH2 protein synthesis. In the published literature, this variant has been reported in individuals affected with colorectal … (more)
This frameshift variant causes the premature termination of MSH2 protein synthesis. In the published literature, this variant has been reported in individuals affected with colorectal cancer and Muir-Torre syndrome (PMID: 14504054 (2003), 15862756 (2005), 21550136 (2011)). Based on the available information, this variant has been classified as pathogenic. (less)
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Pathogenic
(Dec 06, 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: SCV000625418.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu12Glyfs*70) in the MSH2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Glu12Glyfs*70) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer and Muir-Torre syndrome (PMID: 14504054, 21550136, 28514183). This variant is also known as 34_35insG. ClinVar contains an entry for this variant (Variation ID: 91068). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 26, 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: SCV004187996.1
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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Pathogenic
(-)
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no assertion criteria provided
Method: research
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000257186.1
First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015 |
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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Prevalence of pathogenic germline cancer risk variants in high-risk urothelial carcinoma. | Nassar AH | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31844177 |
Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. | Espenschied CR | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28514183 |
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 |
Immunosuppression and sebaceous tumors: a confirmed diagnosis of Muir-Torre syndrome unmasked by immunosuppressive therapy. | Landis MN | Journal of the American Academy of Dermatology | 2011 | PMID: 21550136 |
Identification of predictive factors for the occurrence of predisposing MLH1 and MSH2 germline mutations among Sardinian patients with colorectal carcinoma. | Colombino M | European journal of cancer (Oxford, England : 1990) | 2005 | PMID: 15862756 |
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 |
Microsatellite instability and mutation analysis among southern Italian patients with colorectal carcinoma: detection of different alterations accounting for MLH1 and MSH2 inactivation in familial cases. | Colombino M | Annals of oncology : official journal of the European Society for Medical Oncology | 2003 | PMID: 14504054 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.34dup | - | - | - | - |
Text-mined citations for rs63750614 ...
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.