ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.2455A>G (p.Lys819Glu)
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
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NM_000251.3(MSH2):c.2455A>G (p.Lys819Glu)
Variation ID: 479805 Accession: VCV000479805.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47478516 (GRCh38) [ NCBI UCSC ] 2: 47705655 (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 Jan 1, 2018 May 1, 2024 Jun 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.2455A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Lys819Glu missense NM_001258281.1:c.2257A>G NP_001245210.1:p.Lys753Glu missense NC_000002.12:g.47478516A>G NC_000002.11:g.47705655A>G NG_007110.2:g.80393A>G LRG_218:g.80393A>G LRG_218t1:c.2455A>G LRG_218p1:p.Lys819Glu - Protein change
- K819E, K753E
- Other names
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- Canonical SPDI
- NC_000002.12:47478515:A:G
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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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
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Feb 10, 2022 | RCV000561225.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 10, 2022 | RCV001362451.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 27, 2023 | RCV004000853.2 |
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
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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
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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
(Oct 28, 2020)
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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: SCV001357881.2
First in ClinVar: Jun 22, 2020 Last updated: Jun 19, 2021 |
Comment:
This missense variant replaces lysine with glutamic acid at codon 819 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein … (more)
This missense variant replaces lysine with glutamic acid at codon 819 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251286 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
(Feb 10, 2022)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002534477.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH2 c.2455A>G (p.K819E) variant has been reported in heterozygosity in at least one individual with breast cancer (PMID: 33471991). This variant was observed in … (more)
The MSH2 c.2455A>G (p.K819E) variant has been reported in heterozygosity in at least one individual with breast cancer (PMID: 33471991). This variant was observed in 1/113662 chromosomes in the Non-Finnish European population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 479805). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Sep 10, 2022)
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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: SCV001558467.3
First in ClinVar: Apr 13, 2021 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. ClinVar contains an entry for this variant (Variation ID: 479805). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 819 of the MSH2 protein (p.Lys819Glu). 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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Uncertain Significance
(Jun 27, 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: SCV004834216.1
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 lysine with glutamic acid at codon 819 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein … (more)
This missense variant replaces lysine with glutamic acid at codon 819 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251286 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
(Jan 28, 2022)
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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: SCV000662273.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.K819E variant (also known as c.2455A>G), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide … (more)
The p.K819E variant (also known as c.2455A>G), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide position 2455. The lysine at codon 819 is replaced by glutamic acid, an amino acid with similar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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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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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 |
Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers. | Pritchard AL | PloS one | 2018 | PMID: 29641532 |
Text-mined citations for rs1369739730 ...
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.