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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 1789912). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 782 of the MSH2 protein (p.Thr782Ala).
ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.2344A>G (p.Thr782Ala)
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.
(4)
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.
Uncertain significance
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000251.3(MSH2):c.2344A>G (p.Thr782Ala)
Variation ID: 1789912 Accession: VCV001789912.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p21 2: 47478405 (GRCh38) [ NCBI UCSC ] 2: 47705544 (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 Nov 29, 2022 Jul 7, 2024 Mar 27, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000251.3:c.2344A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Thr782Ala missense NM_001258281.1:c.2146A>G NP_001245210.1:p.Thr716Ala missense NM_001406631.1:c.2344A>G NP_001393560.1:p.Thr782Ala missense NM_001406632.1:c.2344A>G NP_001393561.1:p.Thr782Ala missense NM_001406633.1:c.2344A>G NP_001393562.1:p.Thr782Ala missense NM_001406634.1:c.2344A>G NP_001393563.1:p.Thr782Ala missense NM_001406635.1:c.2344A>G NP_001393564.1:p.Thr782Ala missense NM_001406636.1:c.2311A>G NP_001393565.1:p.Thr771Ala missense NM_001406637.1:c.2344A>G NP_001393566.1:p.Thr782Ala missense NM_001406638.1:c.2383A>G NP_001393567.1:p.Thr795Ala missense NM_001406639.1:c.2344A>G NP_001393568.1:p.Thr782Ala missense NM_001406640.1:c.2344A>G NP_001393569.1:p.Thr782Ala missense NM_001406641.1:c.2344A>G NP_001393570.1:p.Thr782Ala missense NM_001406642.1:c.2344A>G NP_001393571.1:p.Thr782Ala missense NM_001406643.1:c.2344A>G NP_001393572.1:p.Thr782Ala missense NM_001406644.1:c.2344A>G NP_001393573.1:p.Thr782Ala missense NM_001406645.1:c.2344A>G NP_001393574.1:p.Thr782Ala missense NM_001406646.1:c.2344A>G NP_001393575.1:p.Thr782Ala missense NM_001406647.1:c.2194A>G NP_001393576.1:p.Thr732Ala missense NM_001406648.1:c.2344A>G NP_001393577.1:p.Thr782Ala missense NM_001406649.1:c.2194A>G NP_001393578.1:p.Thr732Ala missense NM_001406650.1:c.2194A>G NP_001393579.1:p.Thr732Ala missense NM_001406651.1:c.2194A>G NP_001393580.1:p.Thr732Ala missense NM_001406652.1:c.2194A>G NP_001393581.1:p.Thr732Ala missense NM_001406653.1:c.2284A>G NP_001393582.1:p.Thr762Ala missense NM_001406654.1:c.1924A>G NP_001393583.1:p.Thr642Ala missense NM_001406656.1:c.1447A>G NP_001393585.1:p.Thr483Ala missense NM_001406658.1:c.988A>G NP_001393587.1:p.Thr330Ala missense NM_001406659.1:c.988A>G NP_001393588.1:p.Thr330Ala missense NM_001406660.1:c.988A>G NP_001393589.1:p.Thr330Ala missense NM_001406661.1:c.988A>G NP_001393590.1:p.Thr330Ala missense NM_001406662.1:c.988A>G NP_001393591.1:p.Thr330Ala missense NM_001406669.1:c.988A>G NP_001393598.1:p.Thr330Ala missense NM_001406674.1:c.2344A>G NP_001393603.1:p.Thr782Ala missense NR_176230.1:n.2380A>G NR_176231.1:n.2348A>G NR_176232.1:n.2380A>G NR_176233.1:n.2222A>G NR_176234.1:n.2380A>G NR_176235.1:n.2380A>G NR_176236.1:n.2380A>G NR_176237.1:n.2380A>G NR_176238.1:n.2513A>G NR_176239.1:n.2380A>G NR_176240.1:n.2175A>G NR_176241.1:n.2380A>G NR_176242.1:n.2380A>G NR_176243.1:n.2230A>G NR_176244.1:n.2380A>G NR_176245.1:n.2380A>G NR_176246.1:n.2380A>G NR_176247.1:n.2380A>G NR_176248.1:n.2380A>G NR_176249.1:n.2610A>G NR_176250.1:n.2120A>G NC_000002.12:g.47478405A>G NC_000002.11:g.47705544A>G NG_007110.2:g.80282A>G LRG_218:g.80282A>G LRG_218t1:c.2344A>G LRG_218p1:p.Thr782Ala - Protein change
- T330A, T483A, T642A, T716A, T762A, T771A, T795A, T732A, T782A
- Other names
- -
- Canonical SPDI
- NC_000002.12:47478404:A:G
-
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.
- -
- 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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Feb 27, 2024 | RCV002428528.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 7, 2023 | RCV003098815.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 15, 2023 | RCV004007423.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 27, 2024 | RCV004526930.2 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Aug 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002996246.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 1789912). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 782 of the MSH2 protein (p.Thr782Ala). (less)
|
|
|
Uncertain Significance
(Aug 15, 2023)
|
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: SCV004827292.1
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)
|
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Feb 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002731876.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.T782A variant (also known as c.2344A>G), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide … (more)
The p.T782A variant (also known as c.2344A>G), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide position 2344. The threonine at codon 782 is replaced by alanine, an amino acid with similar properties. This variant was identified in a cohort of 882 Chinese individuals with a personal and/or family history of breast or ovarian cancers who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657). 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 neutral (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 available evidence, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Mar 27, 2024)
|
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: SCV005039016.2
First in ClinVar: May 07, 2024 Last updated: Jul 07, 2024 |
Comment:
Variant summary: MSH2 c.2344A>G (p.Thr782Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the … (more)
Variant summary: MSH2 c.2344A>G (p.Thr782Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251448 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2344A>G in individuals affected with Lynch Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (Jia_2021). These results showed no damaging effect of this variant on a massively parallel functional assay utilizing an established chemical selection for mismatch repair dysfunction. The following publication has been ascertained in the context of this evaluation (PMID: 33357406). ClinVar contains an entry for this variant (Variation ID: 1789912). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
Comment:
Comment:
The p.T782A variant (also known as c.2344A>G), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide position 2344. The threonine at codon 782 is replaced by alanine, an amino acid with similar properties. This variant was identified in a cohort of 882 Chinese individuals with a personal and/or family history of breast or ovarian cancers who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657). 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 neutral (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 available evidence, the clinical significance of this alteration remains unclear.
Comment:
Variant summary: MSH2 c.2344A>G (p.Thr782Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251448 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2344A>G in individuals affected with Lynch Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (Jia_2021). These results showed no damaging effect of this variant on a massively parallel functional assay utilizing an established chemical selection for mismatch repair dysfunction. The following publication has been ascertained in the context of this evaluation (PMID: 33357406). ClinVar contains an entry for this variant (Variation ID: 1789912). Based on the evidence outlined above, the variant was classified as uncertain significance.
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:
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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 1789912). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 782 of the MSH2 protein (p.Thr782Ala).
Comment:
The p.T782A variant (also known as c.2344A>G), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide position 2344. The threonine at codon 782 is replaced by alanine, an amino acid with similar properties. This variant was identified in a cohort of 882 Chinese individuals with a personal and/or family history of breast or ovarian cancers who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657). 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 neutral (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 available evidence, the clinical significance of this alteration remains unclear.
Comment:
Variant summary: MSH2 c.2344A>G (p.Thr782Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251448 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2344A>G in individuals affected with Lynch Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (Jia_2021). These results showed no damaging effect of this variant on a massively parallel functional assay utilizing an established chemical selection for mismatch repair dysfunction. The following publication has been ascertained in the context of this evaluation (PMID: 33357406). ClinVar contains an entry for this variant (Variation ID: 1789912). Based on the evidence outlined above, the variant was classified as uncertain significance.
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 |
| Prevalence of hereditary breast and ovarian cancer (HBOC) predisposition gene mutations among 882 HBOC high-risk Chinese individuals. | Shao D | Cancer science | 2020 | PMID: 31742824 |
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.