This missense variant replaces alanine with valine at codon 714 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies investigating microsatellite instability, mismatch repair activity, DNA damage response, and protein stability in engineered human embryonic stem cells (PMID: 31237724), or assaying mismatch repair and Msh3 and Msh6 interactions in yeast (PMID: 17720936) have not demonstrated a deleterious impact for this variant. This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer and their asymptomatic relative (PMID: 12132870), and in an individual affected with breast cancer (PMID: 35402282). This variant has been identified in 1/31376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.2141C>T (p.Ala714Val)
Germline
Classification
Help
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.
(5)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(3); Likely benign(1)
Uncertain significance(3); Likely benign(1)
5
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000251.3(MSH2):c.2141C>T (p.Ala714Val)
Variation ID: 90907 Accession: VCV000090907.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47476502 (GRCh38) [ NCBI UCSC ] 2: 47703641 (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 Oct 8, 2024 Jan 11, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000251.3:c.2141C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Ala714Val missense NM_001258281.1:c.1943C>T NP_001245210.1:p.Ala648Val missense NC_000002.12:g.47476502C>T NC_000002.11:g.47703641C>T NG_007110.2:g.78379C>T LRG_218:g.78379C>T LRG_218t1:c.2141C>T LRG_218p1:p.Ala714Val P43246:p.Ala714Val - Protein change
- A714V, A648V
- Other names
- -
- Canonical SPDI
- NC_000002.12:47476501:C:T
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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.
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The Genome Aggregation Database (gnomAD) 0.00001
- Links
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 |
7404 | 7566 | |
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) |
criteria provided, single submitter
|
Jul 18, 2023 | RCV000535935.10 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 2, 2022 | RCV000574384.7 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 11, 2024 | RCV003997159.2 | |
|
MSH2-related disorder
|
Uncertain significance (1) |
no assertion criteria provided
|
Nov 6, 2023 | RCV004537294.2 |
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
(Jul 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000625355.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
|
|
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Uncertain significance
(Aug 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: SCV001344425.3
First in ClinVar: Mar 25, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with valine at codon 714 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces alanine with valine at codon 714 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies investigating microsatellite instability, mismatch repair activity, DNA damage response, and protein stability in engineered human embryonic stem cells (PMID: 31237724), or assaying mismatch repair and Msh3 and Msh6 interactions in yeast (PMID: 17720936) have not demonstrated a deleterious impact for this variant. This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer and their asymptomatic relative (PMID: 12132870), and in an individual affected with breast cancer (PMID: 35402282). This variant has been identified in 1/31376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
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Uncertain Significance
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004825681.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces alanine with valine at codon 714 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces alanine with valine at codon 714 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies investigating microsatellite instability, mismatch repair activity, DNA damage response, and protein stability in engineered human embryonic stem cells (PMID: 31237724), or assaying mismatch repair and Msh3 and Msh6 interactions in yeast (PMID: 17720936) have not demonstrated a deleterious impact for this variant. This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer and their asymptomatic relative (PMID: 12132870), and in an individual affected with breast cancer (PMID: 35402282). This variant has been identified in 1/31376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 1
|
|
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Uncertain significance
(Nov 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000662221.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.A714V variant (also known as c.2141C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide … (more)
The p.A714V variant (also known as c.2141C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2141. The alanine at codon 714 is replaced by valine, an amino acid with similar properties. This alteration has been detected in 1 Korean HNPCC kindred and was absent from 300 healthy Korean individuals (Kim JC et al, Fam. Cancer 2004; 3(2):129-37). Functional analyses of this variant in yeast have demonstrated protein interaction, function, and expression comparable to wild type MSH2 (Gammie AE et al, Genetics 2007 Oct; 177(2):707-21). A study of the functional significance of MSH2 missense variants using CRISPR-Cas9 gene editing in human embryonic stem cells suggests this alteration is proficient at DNA repair function, damage response signaling and protein stability (Rath A et al. Hum Mutat, 2019 11;40:2044-2056). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Nov 06, 2023)
|
no assertion criteria provided
Method: clinical testing
|
MSH2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004734289.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The MSH2 c.2141C>T variant is predicted to result in the amino acid substitution p.Ala714Val. This variant was reported in an individual with colorectal cancer (Table … (more)
The MSH2 c.2141C>T variant is predicted to result in the amino acid substitution p.Ala714Val. This variant was reported in an individual with colorectal cancer (Table 1, Kim et al. 2004. PubMed ID: 15340264; Table 1, Zhu et al. 2013. PubMed ID: 23760103). Experimental studies suggest this variant does not impact protein mismatch repair activity (Table 2, referred to as msh2-A733V, Gammie et al. 2007. PubMed ID: 17720936; Figure 3, Rath et al. 2019. PubMed ID: 31237724; Tables S4 and S5, Jia et al. 2020. PubMed ID: 33357406). This variant is reported in 1 of ~31,000 alleles in gnomAD (https://gnomad.broadinstitute.org/variant/2-47703641-C-T?dataset=gnomad_r2_1). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/90907/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
Comment:
Comment:
This missense variant replaces alanine with valine at codon 714 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies investigating microsatellite instability, mismatch repair activity, DNA damage response, and protein stability in engineered human embryonic stem cells (PMID: 31237724), or assaying mismatch repair and Msh3 and Msh6 interactions in yeast (PMID: 17720936) have not demonstrated a deleterious impact for this variant. This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer and their asymptomatic relative (PMID: 12132870), and in an individual affected with breast cancer (PMID: 35402282). This variant has been identified in 1/31376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.A714V variant (also known as c.2141C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2141. The alanine at codon 714 is replaced by valine, an amino acid with similar properties. This alteration has been detected in 1 Korean HNPCC kindred and was absent from 300 healthy Korean individuals (Kim JC et al, Fam. Cancer 2004; 3(2):129-37). Functional analyses of this variant in yeast have demonstrated protein interaction, function, and expression comparable to wild type MSH2 (Gammie AE et al, Genetics 2007 Oct; 177(2):707-21). A study of the functional significance of MSH2 missense variants using CRISPR-Cas9 gene editing in human embryonic stem cells suggests this alteration is proficient at DNA repair function, damage response signaling and protein stability (Rath A et al. Hum Mutat, 2019 11;40:2044-2056). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
The MSH2 c.2141C>T variant is predicted to result in the amino acid substitution p.Ala714Val. This variant was reported in an individual with colorectal cancer (Table 1, Kim et al. 2004. PubMed ID: 15340264; Table 1, Zhu et al. 2013. PubMed ID: 23760103). Experimental studies suggest this variant does not impact protein mismatch repair activity (Table 2, referred to as msh2-A733V, Gammie et al. 2007. PubMed ID: 17720936; Figure 3, Rath et al. 2019. PubMed ID: 31237724; Tables S4 and S5, Jia et al. 2020. PubMed ID: 33357406). This variant is reported in 1 of ~31,000 alleles in gnomAD (https://gnomad.broadinstitute.org/variant/2-47703641-C-T?dataset=gnomad_r2_1). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/90907/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
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. |
Comment:
This missense variant replaces alanine with valine at codon 714 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies investigating microsatellite instability, mismatch repair activity, DNA damage response, and protein stability in engineered human embryonic stem cells (PMID: 31237724), or assaying mismatch repair and Msh3 and Msh6 interactions in yeast (PMID: 17720936) have not demonstrated a deleterious impact for this variant. This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer and their asymptomatic relative (PMID: 12132870), and in an individual affected with breast cancer (PMID: 35402282). This variant has been identified in 1/31376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces alanine with valine at codon 714 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies investigating microsatellite instability, mismatch repair activity, DNA damage response, and protein stability in engineered human embryonic stem cells (PMID: 31237724), or assaying mismatch repair and Msh3 and Msh6 interactions in yeast (PMID: 17720936) have not demonstrated a deleterious impact for this variant. This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer and their asymptomatic relative (PMID: 12132870), and in an individual affected with breast cancer (PMID: 35402282). This variant has been identified in 1/31376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.A714V variant (also known as c.2141C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2141. The alanine at codon 714 is replaced by valine, an amino acid with similar properties. This alteration has been detected in 1 Korean HNPCC kindred and was absent from 300 healthy Korean individuals (Kim JC et al, Fam. Cancer 2004; 3(2):129-37). Functional analyses of this variant in yeast have demonstrated protein interaction, function, and expression comparable to wild type MSH2 (Gammie AE et al, Genetics 2007 Oct; 177(2):707-21). A study of the functional significance of MSH2 missense variants using CRISPR-Cas9 gene editing in human embryonic stem cells suggests this alteration is proficient at DNA repair function, damage response signaling and protein stability (Rath A et al. Hum Mutat, 2019 11;40:2044-2056). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
The MSH2 c.2141C>T variant is predicted to result in the amino acid substitution p.Ala714Val. This variant was reported in an individual with colorectal cancer (Table 1, Kim et al. 2004. PubMed ID: 15340264; Table 1, Zhu et al. 2013. PubMed ID: 23760103). Experimental studies suggest this variant does not impact protein mismatch repair activity (Table 2, referred to as msh2-A733V, Gammie et al. 2007. PubMed ID: 17720936; Figure 3, Rath et al. 2019. PubMed ID: 31237724; Tables S4 and S5, Jia et al. 2020. PubMed ID: 33357406). This variant is reported in 1 of ~31,000 alleles in gnomAD (https://gnomad.broadinstitute.org/variant/2-47703641-C-T?dataset=gnomad_r2_1). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/90907/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Rates of Variants of Uncertain Significance Among Patients With Breast Cancer Undergoing Genetic Testing: Regional Perspectives. | Abdel-Razeq H | Frontiers in oncology | 2022 | PMID: 35402282 |
| Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
| 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 |
| 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 |
| Missense mutations of MLH1 and MSH2 genes detected in patients with gastrointestinal cancer are associated with exonic splicing enhancers and silencers. | Zhu M | Oncology letters | 2013 | PMID: 23760103 |
| Functional characterization of pathogenic human MSH2 missense mutations in Saccharomyces cerevisiae. | Gammie AE | Genetics | 2007 | PMID: 17720936 |
| Single-nucleotide polymorphisms of mismatch repair genes in healthy Chinese individuals and sporadic colorectal cancer patients. | Mei Q | Cancer genetics and cytogenetics | 2006 | PMID: 17074586 |
| Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients. | Kim JC | Familial cancer | 2004 | PMID: 15340264 |
| hMLH1 and hMSH2 mutations in families with familial clustering of gastric cancer and hereditary non-polyposis colorectal cancer. | Kim JC | Cancer detection and prevention | 2001 | PMID: 12132870 |
Text-mined citations for rs63751224 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.