This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 761 of the MSH2 protein (p.Gly761Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.2282G>A (p.Gly761Glu)
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.
(2)
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
Likely pathogenic(1); Uncertain significance(1)
Likely pathogenic(1); Uncertain significance(1)
2
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.2282G>A (p.Gly761Glu)
Variation ID: 2095532 Accession: VCV002095532.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47478343 (GRCh38) [ NCBI UCSC ] 2: 47705482 (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 Feb 8, 2023 Aug 11, 2024 May 1, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000251.3:c.2282G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Gly761Glu missense NM_000251.1:c.2282G>A NM_001258281.1:c.2084G>A NP_001245210.1:p.Gly695Glu missense NM_001406631.1:c.2282G>A NP_001393560.1:p.Gly761Glu missense NM_001406632.1:c.2282G>A NP_001393561.1:p.Gly761Glu missense NM_001406633.1:c.2282G>A NP_001393562.1:p.Gly761Glu missense NM_001406634.1:c.2282G>A NP_001393563.1:p.Gly761Glu missense NM_001406635.1:c.2282G>A NP_001393564.1:p.Gly761Glu missense NM_001406636.1:c.2249G>A NP_001393565.1:p.Gly750Glu missense NM_001406637.1:c.2282G>A NP_001393566.1:p.Gly761Glu missense NM_001406638.1:c.2321G>A NP_001393567.1:p.Gly774Glu missense NM_001406639.1:c.2282G>A NP_001393568.1:p.Gly761Glu missense NM_001406640.1:c.2282G>A NP_001393569.1:p.Gly761Glu missense NM_001406641.1:c.2282G>A NP_001393570.1:p.Gly761Glu missense NM_001406642.1:c.2282G>A NP_001393571.1:p.Gly761Glu missense NM_001406643.1:c.2282G>A NP_001393572.1:p.Gly761Glu missense NM_001406644.1:c.2282G>A NP_001393573.1:p.Gly761Glu missense NM_001406645.1:c.2282G>A NP_001393574.1:p.Gly761Glu missense NM_001406646.1:c.2282G>A NP_001393575.1:p.Gly761Glu missense NM_001406647.1:c.2132G>A NP_001393576.1:p.Gly711Glu missense NM_001406648.1:c.2282G>A NP_001393577.1:p.Gly761Glu missense NM_001406649.1:c.2132G>A NP_001393578.1:p.Gly711Glu missense NM_001406650.1:c.2132G>A NP_001393579.1:p.Gly711Glu missense NM_001406651.1:c.2132G>A NP_001393580.1:p.Gly711Glu missense NM_001406652.1:c.2132G>A NP_001393581.1:p.Gly711Glu missense NM_001406653.1:c.2222G>A NP_001393582.1:p.Gly741Glu missense NM_001406654.1:c.1862G>A NP_001393583.1:p.Gly621Glu missense NM_001406656.1:c.1385G>A NP_001393585.1:p.Gly462Glu missense NM_001406658.1:c.926G>A NP_001393587.1:p.Gly309Glu missense NM_001406659.1:c.926G>A NP_001393588.1:p.Gly309Glu missense NM_001406660.1:c.926G>A NP_001393589.1:p.Gly309Glu missense NM_001406661.1:c.926G>A NP_001393590.1:p.Gly309Glu missense NM_001406662.1:c.926G>A NP_001393591.1:p.Gly309Glu missense NM_001406669.1:c.926G>A NP_001393598.1:p.Gly309Glu missense NM_001406674.1:c.2282G>A NP_001393603.1:p.Gly761Glu missense NR_176230.1:n.2318G>A NR_176231.1:n.2286G>A NR_176232.1:n.2318G>A NR_176233.1:n.2160G>A NR_176234.1:n.2318G>A NR_176235.1:n.2318G>A NR_176236.1:n.2318G>A NR_176237.1:n.2318G>A NR_176238.1:n.2451G>A NR_176239.1:n.2318G>A NR_176240.1:n.2113G>A NR_176241.1:n.2318G>A NR_176242.1:n.2318G>A NR_176243.1:n.2168G>A NR_176244.1:n.2318G>A NR_176245.1:n.2318G>A NR_176246.1:n.2318G>A NR_176247.1:n.2318G>A NR_176248.1:n.2318G>A NR_176249.1:n.2548G>A NR_176250.1:n.2058G>A NC_000002.12:g.47478343G>A NC_000002.11:g.47705482G>A NG_007110.2:g.80220G>A LRG_218:g.80220G>A LRG_218t1:c.2282G>A LRG_218p1:p.Gly761Glu - Protein change
- G621E, G741E, G711E, G761E, G462E, G774E, G309E, G695E, G750E
- Other names
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- Canonical SPDI
- NC_000002.12:47478342:G:A
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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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
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| 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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
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Feb 9, 2022 | RCV003013819.3 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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May 1, 2024 | RCV004654088.1 |
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. |
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|---|---|---|---|---|---|
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Uncertain significance
(Feb 09, 2022)
|
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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003307417.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 761 of the MSH2 protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 761 of the MSH2 protein (p.Gly761Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
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Likely pathogenic
(May 01, 2024)
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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: SCV005141918.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
The p.G761E variant (also known as c.2282G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide … (more)
The p.G761E variant (also known as c.2282G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2282. The glycine at codon 761 is replaced by glutamic acid, an amino acid with similar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
Comment:
Comment:
The p.G761E variant (also known as c.2282G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2282. The glycine at codon 761 is replaced by glutamic acid, an amino acid with similar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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 sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 761 of the MSH2 protein (p.Gly761Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The p.G761E variant (also known as c.2282G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2282. The glycine at codon 761 is replaced by glutamic acid, an amino acid with similar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
Text-mined citations for this variant ...
HelpRecord last updated Sep 29, 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.