ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.2500G>A (p.Ala834Thr)
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
-
NM_000251.3(MSH2):c.2500G>A (p.Ala834Thr)
Variation ID: 90986 Accession: VCV000090986.33
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p21 2: 47480737 (GRCh38) [ NCBI UCSC ] 2: 47707876 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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
-
Nucleotide Protein Molecular
consequenceNM_000251.3:c.2500G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Ala834Thr missense NM_001258281.1:c.2302G>A NP_001245210.1:p.Ala768Thr missense NC_000002.12:g.47480737G>A NC_000002.11:g.47707876G>A NG_007110.2:g.82614G>A LRG_218:g.82614G>A LRG_218t1:c.2500G>A LRG_218p1:p.Ala834Thr P43246:p.Ala834Thr - Protein change
- A834T, A768T
- Other names
- p.A834T:GCT>ACT
- Canonical SPDI
- NC_000002.12:47480736:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00008
Exome Aggregation Consortium (ExAC) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00010
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7207 | 7355 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Likely benign (1) |
reviewed by expert panel
|
Sep 5, 2013 | RCV000076488.5 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 10, 2022 | RCV000131725.11 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jul 22, 2019 | RCV000659884.7 | |
Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
Aug 10, 2022 | RCV000679306.18 | |
Benign (1) |
criteria provided, single submitter
|
Jan 24, 2024 | RCV001084815.7 |
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
Help
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
Help
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
Help
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. |
|
---|---|---|---|---|---|
Likely benign
(Sep 05, 2013)
|
reviewed by expert panel
Method: research
|
Lynch Syndrome
Affected status: unknown
Allele origin:
germline
|
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107517.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comment:
Multifactorial likelihood analysis posterior probability 0.001-0.049
|
|
Uncertain significance
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781776.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
|
|
Likely benign
(Oct 26, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000806030.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
|
|
Likely benign
(Nov 08, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186765.8
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Number of individuals with the variant: 1
|
|
Likely benign
(Aug 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601467.6
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
|
|
Benign
(Mar 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000537488.2
First in ClinVar: Mar 24, 2017 Last updated: Feb 14, 2024 |
|
|
Benign
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000253156.11
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
|
|
Likely benign
(Jul 22, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001302498.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
Likely benign
(Sep 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000211254.12
First in ClinVar: Feb 24, 2015 Last updated: Dec 19, 2017 |
Comment:
This variant is associated with the following publications: (PMID: 21120944, 17594722, 9311737, 22102614, 22949387, 30798936, 10448273, 24038355, 18547406, 11162093, 14526391, 17101317, 18951462, 16216036, 18566915, 18822302, … (more)
This variant is associated with the following publications: (PMID: 21120944, 17594722, 9311737, 22102614, 22949387, 30798936, 10448273, 24038355, 18547406, 11162093, 14526391, 17101317, 18951462, 16216036, 18566915, 18822302, 17192056, 21239990, 10573010, 25871441, 26951660, 15849733, 24362816, 18383312, 30998989) (less)
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743364.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001919751.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959497.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome. | Bouvet D | Gastroenterology | 2019 | PMID: 30998989 |
Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants. | Houlleberghs H | Proceedings of the National Academy of Sciences of the United States of America | 2016 | PMID: 26951660 |
Evaluation of CADD Scores in Curated Mismatch Repair Gene Variants Yields a Model for Clinical Validation and Prioritization. | van der Velde KJ | Human mutation | 2015 | PMID: 25871441 |
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 |
Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions. | Thompson BA | Human mutation | 2013 | PMID: 22949387 |
A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants. | Drost M | Human mutation | 2012 | PMID: 22102614 |
Integrated analysis of unclassified variants in mismatch repair genes. | Pastrello C | Genetics in medicine : official journal of the American College of Medical Genetics | 2011 | PMID: 21239990 |
Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants. | Kansikas M | Human mutation | 2011 | PMID: 21120944 |
Mechanisms of pathogenicity in human MSH2 missense mutants. | Ollila S | Human mutation | 2008 | PMID: 18951462 |
Functional analysis of HNPCC-related missense mutations in MSH2. | Lützen A | Mutation research | 2008 | PMID: 18822302 |
The association between genetic variants in hMLH1 and hMSH2 and the development of sporadic colorectal cancer in the Danish population. | Christensen LL | BMC medical genetics | 2008 | PMID: 18547406 |
Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). | Chao EC | Human mutation | 2008 | PMID: 18383312 |
Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. | Ou J | Human mutation | 2007 | PMID: 17594722 |
Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein. | Ollila S | Gastroenterology | 2006 | PMID: 17101317 |
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 |
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.2500G%3EA | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs63750757 ...
HelpRecord last updated Mar 11, 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.