ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.1927G>A (p.Glu643Lys)
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.
Uncertain significance(8); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.1927G>A (p.Glu643Lys)
Variation ID: 161299 Accession: VCV000161299.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47475192 (GRCh38) [ NCBI UCSC ] 2: 47702331 (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 Dec 7, 2014 Jun 17, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.1927G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Glu643Lys missense NM_001258281.1:c.1729G>A NP_001245210.1:p.Glu577Lys missense NC_000002.12:g.47475192G>A NC_000002.11:g.47702331G>A NG_007110.2:g.77069G>A LRG_218:g.77069G>A LRG_218t1:c.1927G>A LRG_218p1:p.Glu643Lys - Protein change
- E643K, E577K
- Other names
- p.E643K:GAA>AAA
- Canonical SPDI
- NC_000002.12:47475191: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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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 |
7401 | 7563 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV000148637.3 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 17, 2024 | RCV000204646.15 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Apr 3, 2023 | RCV000160596.15 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2022 | RCV000589876.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000765671.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 12, 2022 | RCV002509245.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 28, 2023 | RCV003998170.2 | |
MSH2-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Jan 11, 2023 | RCV004532666.1 |
not provided (1) |
no classification provided
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- | RCV003483522.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 21, 2023 | RCV004567167.1 |
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
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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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Uncertain significance
(Dec 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000211192.13
First in ClinVar: Feb 24, 2015 Last updated: Dec 24, 2022 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: increased mutation rate compared to wild type controls in a yeast based assay (Ollodart et al., 2020); Observed in individuals with a personal history of ovarian cancer or pancreatic ductal adenocarcinoma (Pal et al., 2012; Shindo et al., 2017; Hu et al., 2020); This variant is associated with the following publications: (PMID: 25637381, 23047549, 28767289, 32659497, 27535533, 18822302, 21120944, 33848333) (less)
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Uncertain significance
(Oct 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004220964.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000035 (4/113736 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.000035 (4/113736 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with ovarian cancer (PMID: 23047549 (2012)) and pancreatic cancer (PMID: 32659497 (2020), 28767289 (2017)). A yeast based functional study has reported inconclusive findings regarding the effect on this variant on MSH2 protein function (PMID: 33848333 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Likely benign
(Jan 17, 2024)
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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: SCV000261595.12
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
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Uncertain significance
(Nov 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005053535.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Muir-Torré syndrome Mismatch repair cancer syndrome 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000897013.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Mar 09, 2021)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000690031.4
First in ClinVar: Feb 19, 2018 Last updated: Jan 08, 2022 |
Comment:
This missense variant replaces glutamic acid with lysine at codon 643 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces glutamic acid with lysine at codon 643 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). However, a functional study has reported that this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been reported in one individual each affected with ovarian cancer (PMID: 23047549) and pancreatic cancer (PMID: 28767289, 32659497). This variant has also been observed in trans with a pathogenic whole gene deletion of the MSH2 gene in an individual affected with an unspecified gynecological cancer (ClinVar variation ID 161299). This variant has been identified in 4/251452 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
(Dec 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696229.2
First in ClinVar: Mar 17, 2018 Last updated: Jan 15, 2023 |
Comment:
Variant summary: MSH2 c.1927G>A (p.Glu643Lys) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the … (more)
Variant summary: MSH2 c.1927G>A (p.Glu643Lys) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251452 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1927G>A has been reported in individuals affected with Ovarian Cancer and Pancreatic Cancer, however these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome (Pal_2012, Shindo_2017). One publication using the yeast ortholog of the variant showed a modest increase in random mutation rates in a continuous culture assay (Ollodart_2021). The increase in mutation rates observed did not indicate loss of function, therefore not allowing for convincing conclusions about the variant on protein function. Five ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jan 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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MSH2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004120695.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MSH2 c.1927G>A variant is predicted to result in the amino acid substitution p.Glu643Lys. This variant was reported in an individual with ovarian cancer and … (more)
The MSH2 c.1927G>A variant is predicted to result in the amino acid substitution p.Glu643Lys. This variant was reported in an individual with ovarian cancer and an individual with pancreatic adenocarcinoma (Table 2, Pal et al. 2012. PubMed ID: 23047549; Table A2, Shindo et al. 2017. PubMed ID: 28767289). This variant is reported in 4 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/2-47702331-G-A; Table S1, Amendola et al. 2015. PubMed ID: 25637381) and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/161299/643). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain Significance
(Jun 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004825006.1
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)
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Comment:
This missense variant replaces glutamic acid with lysine at codon 643 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces glutamic acid with lysine at codon 643 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). However, a functional study has reported that this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been reported in one individual each affected with ovarian cancer (PMID: 23047549) and pancreatic cancer (PMID: 28767289, 32659497). This variant has also been observed in trans with a pathogenic whole gene deletion of the MSH2 gene in an individual affected with an unspecified gynecological cancer (ClinVar variation ID 161299). This variant has been identified in 4/251452 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: 2
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Likely benign
(Apr 03, 2023)
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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: SCV000216735.8
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)
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Uncertain significance
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Ovarian cancer
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190352.1 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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not provided
(-)
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no classification provided
Method: phenotyping only
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Lynch syndrome
Mismatch repair cancer syndrome 2
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228709.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Uncertain significance and reported on 04-20-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more)
Variant interpreted as Uncertain significance and reported on 04-20-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Breast carcinoma (present)
Indication for testing: Diagnostic
Age: 40-49 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-04-20
Testing laboratory interpretation: Uncertain significance
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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 |
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Multiplexing mutation rate assessment: determining pathogenicity of Msh2 variants in Saccharomyces cerevisiae. | Ollodart AR | Genetics | 2021 | PMID: 33848333 |
Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry. | Matejcic M | JCO precision oncology | 2020 | PMID: 32832836 |
Association of Germline Variants in Human DNA Damage Repair Genes and Response to Adjuvant Chemotherapy in Resected Pancreatic Ductal Adenocarcinoma. | Hu H | Journal of the American College of Surgeons | 2020 | PMID: 32659497 |
Rare loss of function variants in candidate genes and risk of colorectal cancer. | Rosenthal EA | Human genetics | 2018 | PMID: 30267214 |
Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. | Shindo K | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28767289 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. | Pal T | British journal of cancer | 2012 | PMID: 23047549 |
Text-mined citations for rs374840361 ...
HelpRecord last updated Oct 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.