ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.229_230del (p.Ser77fs)
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.229_230del (p.Ser77fs)
Variation ID: 90953 Accession: VCV000090953.23
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 2p21 2: 47408416-47408417 (GRCh38) [ NCBI UCSC ] 2: 47635555-47635556 (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.229_230del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Ser77fs frameshift NM_000251.1:c.229_230delAG NM_000251.2:c.229_230delAG NM_001258281.1:c.31_32del NP_001245210.1:p.Ser11fs frameshift NC_000002.12:g.47408416AG[1] NC_000002.11:g.47635555AG[1] NG_007110.2:g.10293AG[1] LRG_218:g.10293AG[1] LRG_218t1:c.229_230del - Protein change
- S11fs, S77fs
- Other names
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- Canonical SPDI
- NC_000002.12:47408415:AGAG:AG
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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
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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 | RCV000076455.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 29, 2022 | RCV000220900.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2023 | RCV000524383.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 30, 2021 | RCV001194000.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2019 | RCV001262888.1 | |
Pathogenic (2) |
criteria provided, single submitter
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Sep 24, 2020 | RCV001353711.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 26, 2023 | RCV003452905.1 |
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: SCV000107478.3
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 introducing premature termination codon
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Pathogenic
(Sep 01, 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: SCV000284145.9
First in ClinVar: Mar 24, 2015 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90953). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90953). This variant is also known as 227-228delAG. This premature translational stop signal has been observed in individual(s) with hereditary non-polyposis colorectal cancer (PMID: 9311737, 10874307, 12414824, 15849733, 26552419). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser77Cysfs*4) 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). (less)
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Pathogenic
(Jul 29, 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: SCV000273660.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The c.229_230delAG pathogenic mutation, located in coding exon 2 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 229 to … (more)
The c.229_230delAG pathogenic mutation, located in coding exon 2 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 229 to 230, causing a translational frameshift with a predicted alternate stop codon (p.S77Cfs*4). This mutation has been reported in multiple HNPCC/Lynch syndrome families in the literature (Wijnen J et al. Am. J. Hum. Genet. 1997 Aug; 61(2):329-35; Mangold E et al. Int. J. Cancer 2005 Sep;116(5):692-702; Pérez-Cabornero L et al. Eur. J. Cancer 2009 May;45(8):1485-93; Jasperson KW et al. Fam. Cancer 2010 Jun;9(2):99-107; Pérez-Cabornero L et al. J Mol Diagn 2013 May;15(3):380-90; Goodfellow PJ et al. J. Clin. Oncol. 2015 Dec;33(36):4301-8). Of note, this alteration is also designated as 229delAG and c.227_228delAG in published literature. 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 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Breast carcinoma
Affected status: no
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440924.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Pathogenic
(Sep 24, 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: SCV001787947.1
First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay 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; This variant is associated with the following publications: (PMID: 31615790, 31054147, 20587412, 19250818, 19731080, 10874307, 15849733, 9311737, 26552419, 12414824, 29889250, 21778331, 28874130) (less)
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Pathogenic
(Nov 30, 2021)
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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: SCV001363216.2
First in ClinVar: Jun 22, 2020 Last updated: Dec 25, 2021 |
Comment:
Variant summary: MSH2 c.229_230delAG (p.Ser77CysfsX4) 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.229_230delAG (p.Ser77CysfsX4) 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 245728 control chromosomes (gnomAD). The variant, c.229_230delAG, has been reported in the literature in multiple individuals affected with Lynch Syndrome (Wijnen_1997, Otway_2000, Wagner_2002, Mangold_2005, Goodfellow_2015, Rossi_2017). These data indicate that the variant is associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and 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
(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: SCV004188003.1
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: 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: SCV000592459.2 First in ClinVar: Mar 24, 2015 Last updated: Apr 13, 2021 |
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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A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. | Rossi BM | BMC cancer | 2017 | PMID: 28874130 |
Frequent PIK3CA Mutations in Colorectal and Endometrial Tumors With 2 or More Somatic Mutations in Mismatch Repair Genes. | Cohen SA | Gastroenterology | 2016 | PMID: 27302833 |
Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study. | Goodfellow PJ | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 26552419 |
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 |
Evaluating the effect of unclassified variants identified in MMR genes using phenotypic features, bioinformatics prediction, and RNA assays. | Pérez-Cabornero L | The Journal of molecular diagnostics : JMD | 2013 | PMID: 23523604 |
Evaluating Lynch syndrome in very early onset colorectal cancer probands without apparent polyposis. | Jasperson KW | Familial cancer | 2010 | PMID: 19731080 |
A new strategy to screen MMR genes in Lynch Syndrome: HA-CAE, MLPA and RT-PCR. | Perez-Cabornero L | European journal of cancer (Oxford, England : 1990) | 2009 | PMID: 19250818 |
Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining. | Mangold E | The Journal of pathology | 2005 | PMID: 16216036 |
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 |
Genetic testing in hereditary non-polyposis colorectal cancer families with a MSH2, MLH1, or MSH6 mutation. | Wagner A | Journal of medical genetics | 2002 | PMID: 12414824 |
Evaluation of enzymatic mutation detectiontrade mark in hereditary nonpolyposis colorectal cancer. | Otway R | Human mutation | 2000 | PMID: 10874307 |
Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations. | Wijnen J | American journal of human genetics | 1997 | PMID: 9311737 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.229_230del | - | - | - | - |
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Text-mined citations for rs63749848 ...
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.