ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.499G>C (p.Asp167His)
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.499G>C (p.Asp167His)
Variation ID: 91112 Accession: VCV000091112.35
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p21 2: 47637365 (GRCh37) [ NCBI UCSC ] 2: 47410226 (GRCh38) [ 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 Dec 6, 2014 May 1, 2024 Jun 13, 2018 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000251.3:c.499G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Asp167His missense NM_001258281.1:c.301G>C NP_001245210.1:p.Asp101His missense NC_000002.12:g.47410226G>C NC_000002.11:g.47637365G>C NG_007110.2:g.12103G>C LRG_218:g.12103G>C LRG_218t1:c.499G>C LRG_218p1:p.Asp167His P43246:p.Asp167His - Protein change
- D167H, D101H
- Other names
- p.D167H:GAT>CAT
- Canonical SPDI
- NC_000002.12:47410225:G:C
-
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.
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00009
Exome Aggregation Consortium (ExAC) 0.00011
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
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 |
7313 | 7466 |
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. |
---|---|---|---|---|
Benign (3) |
reviewed by expert panel
|
Jun 13, 2018 | RCV000076615.13 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 2, 2022 | RCV000115533.19 | |
Likely benign (1) |
no assertion criteria provided
|
Jun 1, 2014 | RCV000148629.5 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000200986.10 | |
Benign (1) |
criteria provided, single submitter
|
Jan 30, 2024 | RCV000524411.12 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Aug 11, 2023 | RCV001284654.8 | |
Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2023 | RCV003492425.1 | |
Likely benign (1) |
criteria provided, single submitter
|
Jun 3, 2019 | RCV003935014.1 |
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
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. |
|
---|---|---|---|---|---|
Benign
(Jun 13, 2018)
|
reviewed by expert panel
Method: curation
|
Lynch syndrome 1
Affected status: yes
Allele origin:
germline
|
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107651.4
First in ClinVar: Dec 19, 2013 Last updated: Dec 11, 2022 |
Comment:
Multifactorial likelihood analysis posterior probability < 0.001 (0.000015)
|
|
Likely benign
(Jan 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149442.13
First in ClinVar: May 17, 2014 Last updated: Dec 19, 2017 |
Comment:
This variant is associated with the following publications: (PMID: 17720936, 12124176, 8872463, 26951660, 28125613, 25637381, 18781619, 20672385, 17192056, 15340264, 11870161, 18822302, 22102614, 22949387, 20176959, 11606497, … (more)
This variant is associated with the following publications: (PMID: 17720936, 12124176, 8872463, 26951660, 28125613, 25637381, 18781619, 20672385, 17192056, 15340264, 11870161, 18822302, 22102614, 22949387, 20176959, 11606497, 25980754, 18383312, 17250665, 17594722, 23741719, 19464205, 26333163, 22045683, 27601186, 31159747, 31237724, 31569399) (less)
|
|
Benign
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000218857.13
First in ClinVar: Mar 29, 2015 Last updated: Feb 14, 2024 |
|
|
Likely benign
(Apr 16, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000212799.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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)
|
|
Uncertain significance
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000822054.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001297030.1
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)
|
|
Benign
(Jun 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696272.3
First in ClinVar: Mar 17, 2018 Last updated: Jul 10, 2021 |
Comment:
Variant summary: MSH2 c.499G>C (p.Asp167His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded … (more)
Variant summary: MSH2 c.499G>C (p.Asp167His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251484 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (8.7e-05 vs 0.00057), allowing no conclusion about variant significance. c.499G>C has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and breast cancer (e.g. Moslein_1996, Scartozzi_2002, Belvederesi_2008, Yurgelun_2015, Lagerstedt-Robinson_2016, Rizzolo_2019, Tsaousis_2019, Ryan_2020, Doling_2021) but it was also reported in controls (e.g. Dorling_2021). In two of the patients from these studies where tumor analysis was carried out, IHC was found to be normal for MSH2 while loss of MLH1 protein expression was noted (Scartozzi_2002, Belvederesi_2008). In a third patient who did not fullfil Amsterdam-II Criteria or Revised Bethesda Criteria, normal IHC results and MSS was observed (Ryan_2020). These results provide supporting evidence for a benign role of the variant. Co-occurrences with pathogenic variants have been reported [MLH1 c.1852_1854delAAG, p.Lys618del (UMD); MLH1 21delG, p.Ile8PhefsX9 (Moslein_1996)], providing further supporting evidence for a benign role. Experimental evidence from multiple studies, including a recent in cellulo functional assay utilizing CRISPR-Cas9 gene editing in human embryonic stem cells, agree in their majority that the variant acts comparable to wild type (e.g. Gammie_2007, Belvederesi_2008, Drost_2011, Rath_2019). Six ClinVar submitters including an expert panel (InSiGHT) (evaluation after 2014) cite the variant as benign/likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. (less)
|
|
Benign
(Jan 26, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002534526.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
Benign
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004024397.2
First in ClinVar: Aug 13, 2023 Last updated: Aug 18, 2023 |
|
|
Benign
(Aug 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV001135703.2
First in ClinVar: Jan 13, 2020 Last updated: Aug 25, 2023 |
|
|
Uncertain significance
(Aug 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001470554.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals/families with Lynch syndrome or Lynch syndrome associated cancers (PMID: 32941469 (2020), 27601186 (2016), 11870161 … (more)
In the published literature, this variant has been reported in individuals/families with Lynch syndrome or Lynch syndrome associated cancers (PMID: 32941469 (2020), 27601186 (2016), 11870161 (2002), 8872463 (1996)) or breast cancer (PMID: 32994724 (2020)). Experimental studies have demonstrated this variant has a neutral effect on MSH2 protein function (PMID: 22949387 (2013), 22102614 (2012), 20672385 (2010), 18822302 (2008), 18781619 (2008), 17720936 (2007)). The frequency of this variant in the general population, 0.0002 (6/30616 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
Likely benign
(Jan 02, 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: SCV000690113.3
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
|
|
Likely benign
(Apr 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004239287.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
Likely benign
(Jun 03, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
MSH2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004750737.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
Likely benign
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Colorectal cancer, non-polyposis
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190344.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001554252.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Number of individuals with the variant: 1
|
|
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 |
---|---|---|---|---|
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
Targeted sequencing of crucial cancer causing genes of breast cancer in Saudi patients. | Alanazi M | Saudi journal of biological sciences | 2020 | PMID: 32994724 |
The proportion of endometrial tumours associated with Lynch syndrome (PETALS): A prospective cross-sectional study. | Ryan NAJ | PLoS medicine | 2020 | PMID: 32941469 |
Functional interrogation of Lynch syndrome-associated MSH2 missense variants via CRISPR-Cas9 gene editing in human embryonic stem cells. | Rath A | Human mutation | 2019 | PMID: 31237724 |
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy. | Rizzolo P | International journal of cancer | 2019 | PMID: 30613976 |
Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population. | Lagerstedt-Robinson K | Oncology reports | 2016 | PMID: 27601186 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
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 |
Lynch syndrome-associated mutations in MSH2 alter DNA repair and checkpoint response functions in vivo. | Mastrocola AS | Human mutation | 2010 | PMID: 20672385 |
Functional analysis of HNPCC-related missense mutations in MSH2. | Lützen A | Mutation research | 2008 | PMID: 18822302 |
MSH2 missense mutations and HNPCC syndrome: pathogenicity assessment in a human expression system. | Belvederesi L | Human mutation | 2008 | PMID: 18781619 |
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 characterization of pathogenic human MSH2 missense mutations in Saccharomyces cerevisiae. | Gammie AE | Genetics | 2007 | PMID: 17720936 |
The use of microsatellite instability, immunohistochemistry and other variables in determining the clinical significance of MLH1 and MSH2 unclassified variants in Lynch syndrome. | Lucci-Cordisco E | Cancer biomarkers : section A of Disease markers | 2006 | PMID: 17192056 |
HNPCC mutations in hMSH2 result in reduced hMSH2-hMSH6 molecular switch functions. | Heinen CD | Cancer cell | 2002 | PMID: 12124176 |
Mutations of hMLH1 and hMSH2 in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with microsatellite instability and abnormalities of mismatch repair protein expression. | Scartozzi M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2002 | PMID: 11870161 |
Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer. | Moslein G | Human molecular genetics | 1996 | PMID: 8872463 |
http://www.insight-database.org/classifications/?gene=MSH2&variant=c.499G%3EC | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs63750255 ...
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.