ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.301_306del (p.Glu101_Val102del)
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.301_306del (p.Glu101_Val102del)
Variation ID: 91060 Accession: VCV000091060.21
- Type and length
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Deletion, 6 bp
- Location
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Cytogenetic: 2p21 2: 47408486-47408491 (GRCh38) [ NCBI UCSC ] 2: 47635625-47635630 (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 Jun 21, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.301_306del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Glu101_Val102del inframe deletion NM_000251.1:c.301_306delGAAGTT NM_000251.2:c.301_306delGAAGTT NM_001258281.1:c.103_108del NP_001245210.1:p.Glu35_Val36del inframe deletion NC_000002.12:g.47408490_47408495del NC_000002.11:g.47635629_47635634del NG_007110.2:g.10367_10372del LRG_218:g.10367_10372del - Protein change
- Other names
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- Canonical SPDI
- NC_000002.12:47408485:AGTTGAAGTT:AGTT
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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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Likely pathogenic (3) |
reviewed by expert panel
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Jun 21, 2019 | RCV000076562.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2023 | RCV000129228.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 22, 2016 | RCV000236396.2 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2022 | RCV000409469.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 7, 2023 | RCV000791449.6 |
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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Likely pathogenic
(Jun 21, 2019)
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reviewed by expert panel
Method: curation
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Lynch syndrome
Affected status: yes
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107590.3
First in ClinVar: Dec 19, 2013 Last updated: Oct 01, 2019 |
Comment:
Multifactorial likelihood analysis posterior probability 0.95-0.99
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Likely pathogenic
(Feb 22, 2016)
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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: SCV000292865.10
First in ClinVar: Jul 24, 2016 Last updated: Jul 24, 2016 |
Comment:
This deletion of 6 nucleotides in MSH2 is denoted c.301_306delGAAGTT at the cDNA level and p.E101_V102del at the protein level. This deletion is also known … (more)
This deletion of 6 nucleotides in MSH2 is denoted c.301_306delGAAGTT at the cDNA level and p.E101_V102del at the protein level. This deletion is also known as MSH2 c.297_302delAGTTGA or 300_305delAGTTGA using alternate nomenclature. The normal sequence, with the bases that are deleted in braces, is AGTT[GAAGTT]TATA. This in frame deletion occurs in a region which is conserved across species and is located within the mismatch binding domain (Lutzen 2008). This variant was observed in at least two patients with early onset colorectal cancer meeting Lynch criteria with tumor studies demonstrating microsatellite instability and immunohistochemistry absent for MSH2 protein (Glasl 2000, Goldberg 2008). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as likely pathogenic (Thompson 2014). Based on the currently available information, we consider MSH2 p.Glu101_Val102del to be a likely pathogenic variant. (less)
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Likely pathogenic
(Apr 24, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696259.3
First in ClinVar: Jul 24, 2016 Last updated: Oct 01, 2019 |
Comment:
Variant summary: MSH2 c.301_306delGAAGTT (p.Glu101_Val102del) results in an in-frame deletion that is predicted to remove 2 amino acids from the DNA mismatch repair protein MutS-like, … (more)
Variant summary: MSH2 c.301_306delGAAGTT (p.Glu101_Val102del) results in an in-frame deletion that is predicted to remove 2 amino acids from the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein. The variant was absent in 251332 control chromosomes (gnomAD). c.301_306delGAAGTT has been reported in the literature in individuals affected with Lynch Syndrome (Latham_2019, Espenschied_2017, Goldberg_2008, Glasl_2000). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) through multifactorial analysis classified the variant as likely pathogenic (Thompson_2014). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1), likely pathogenic (n=3) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Sep 21, 2016)
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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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Counsyl
Accession: SCV000489343.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely pathogenic
(Jan 27, 2022)
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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: SCV004196920.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Mar 30, 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: SCV000183982.10
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.301_306delGAAGTT variant (also known as p.E101_V102del) is located in coding exon 2 of the MSH2 gene. This variant results from an in-frame six base … (more)
The c.301_306delGAAGTT variant (also known as p.E101_V102del) is located in coding exon 2 of the MSH2 gene. This variant results from an in-frame six base pair deletion between nucleotide positions 301 and 306. This results in the deletion of a glutamic acid residue and a valine residue, two highly conserved amino acids, between codons 101 and 102. This alteration has been previously reported in multiple families meeting Amsterdam and/or Bethesda criteria and included family members with colon tumors that demonstrated absent MSH2 staining on immunohistochemistry and high microsatellite instability (MSI-H) (Glasl et al. Hum Mutat. 2000 Jul;16(1):91-2; Goldberg et al. Fam Cancer. 2008;7(4):309-17; Ambry internal data). This alteration has been classified as likely pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15). Of note, this variant is also referred to as 300-305delAGTTGA and c.297_302delAGTTGA in published literature. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Apr 01, 2018)
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criteria provided, single submitter
Method: research
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: no
Allele origin:
germline
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000788237.2
First in ClinVar: Mar 24, 2015 Last updated: Mar 24, 2015 |
Comment:
The MSH2 variant designated as NM_000251.2:c.301_306del is classified as likely pathogenic. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, … (more)
The MSH2 variant designated as NM_000251.2:c.301_306del is classified as likely pathogenic. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 1.99 to 1 (Thompson, et al., 2003, PMID:1290079), which provides some evidence that this allele is pathogenic. Multifactorial likelihood analysis from the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) database gives a 95% probability of pathogenicity for this variant as of the year 2016 (http://www.insight-database.org/classifications/). This variant is not found in the ExAC (exac.broadinstitute.org) or gnomAD (gnomad.broadinstitute.org) population databases or the UMD database (http://umd.be/). This genomic region is highly conserved across species. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a >99% probability of pathogenicity, which is consistent with a classification of pathogenic. This variant is predicted to alter MSH2 function and increase cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. (less)
Clinical Features:
Breast cancer (present) , Colon cancer (present) , Uterine cancer (present)
Family history: yes
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Pathogenic
(Aug 07, 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: SCV000548187.6
First in ClinVar: Mar 24, 2015 Last updated: Feb 28, 2024 |
Comment:
This variant, c.301_306del, results in the deletion of 2 amino acid(s) of the MSH2 protein (p.Glu101_Val102del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.301_306del, results in the deletion of 2 amino acid(s) of the MSH2 protein (p.Glu101_Val102del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Lynch syndrome or clinical features of Lynch syndrome (PMID: 10874318, 11179758, 18389388; Invitae; externalcommunication). This variant is also known as 300-305delAGTTGA, 300delAGTTGA, c.297_302delAGTTGA. ClinVar contains an entry for this variant (Variation ID: 91060). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). For these reasons, this variant has been classified as Pathogenic. (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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Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. | Latham A | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2019 | PMID: 30376427 |
Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance. | Tsai GJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30374176 |
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 |
Genetic features of Lynch syndrome in the Israeli population. | Goldberg Y | Clinical genetics | 2015 | PMID: 25430799 |
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 |
Lynch Syndrome in high risk Ashkenazi Jews in Israel. | Goldberg Y | Familial cancer | 2014 | PMID: 23990280 |
Mutation spectrum in HNPCC in the Israeli population. | Goldberg Y | Familial cancer | 2008 | PMID: 18389388 |
DHPLC mutation analysis of the hereditary nonpolyposis colon cancer (HNPCC) genes hMLH1 and hMSH2. | Holinski-Feder E | Journal of biochemical and biophysical methods | 2001 | PMID: 11179758 |
Novel germline mutation (300-305delAGTTGA) in the human MSH2 gene in hereditary non-polyposis colorectal cancer (HNPCC). | Glasl S | Human mutation | 2000 | PMID: 10874318 |
http://www.insight-database.org/classifications/?gene=MSH2&variant=c.301_306del | - | - | - | - |
Text-mined citations for rs587779157 ...
HelpRecord last updated May 01, 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.