This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.897T>A (p.Tyr299Ter)
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.
(3)
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.
Pathogenic
3
criteria provided, multiple submitters, no conflicts
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.897T>A (p.Tyr299Ter)
Variation ID: 2587529 Accession: VCV002587529.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47414373 (GRCh38) [ NCBI UCSC ] 2: 47641512 (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 Oct 28, 2023 May 1, 2024 Nov 7, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000251.3:c.897T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Tyr299Ter nonsense NM_001258281.1:c.699T>A NP_001245210.1:p.Tyr233Ter nonsense NM_001406631.1:c.897T>A NP_001393560.1:p.Tyr299Ter nonsense NM_001406632.1:c.897T>A NP_001393561.1:p.Tyr299Ter nonsense NM_001406633.1:c.897T>A NP_001393562.1:p.Tyr299Ter nonsense NM_001406634.1:c.897T>A NP_001393563.1:p.Tyr299Ter nonsense NM_001406635.1:c.897T>A NP_001393564.1:p.Tyr299Ter nonsense NM_001406636.1:c.864T>A NP_001393565.1:p.Tyr288Ter nonsense NM_001406637.1:c.897T>A NP_001393566.1:p.Tyr299Ter nonsense NM_001406638.1:c.897T>A NP_001393567.1:p.Tyr299Ter nonsense NM_001406639.1:c.897T>A NP_001393568.1:p.Tyr299Ter nonsense NM_001406640.1:c.897T>A NP_001393569.1:p.Tyr299Ter nonsense NM_001406641.1:c.897T>A NP_001393570.1:p.Tyr299Ter nonsense NM_001406642.1:c.897T>A NP_001393571.1:p.Tyr299Ter nonsense NM_001406643.1:c.897T>A NP_001393572.1:p.Tyr299Ter nonsense NM_001406644.1:c.897T>A NP_001393573.1:p.Tyr299Ter nonsense NM_001406645.1:c.897T>A NP_001393574.1:p.Tyr299Ter nonsense NM_001406646.1:c.897T>A NP_001393575.1:p.Tyr299Ter nonsense NM_001406647.1:c.792+1813T>A intron variant NM_001406648.1:c.897T>A NP_001393577.1:p.Tyr299Ter nonsense NM_001406649.1:c.792+1813T>A intron variant NM_001406650.1:c.792+1813T>A intron variant NM_001406651.1:c.792+1813T>A intron variant NM_001406652.1:c.792+1813T>A intron variant NM_001406653.1:c.837T>A NP_001393582.1:p.Tyr279Ter nonsense NM_001406654.1:c.477T>A NP_001393583.1:p.Tyr159Ter nonsense NM_001406655.1:c.897T>A NP_001393584.1:p.Tyr299Ter nonsense NM_001406656.1:c.-1T>A 5 prime UTR NM_001406657.1:c.897T>A NP_001393586.1:p.Tyr299Ter nonsense NM_001406658.1:c.-527+1813T>A intron variant NM_001406659.1:c.-572T>A 5 prime UTR NM_001406660.1:c.-769T>A 5 prime UTR NM_001406661.1:c.-724T>A 5 prime UTR NM_001406662.1:c.-641T>A 5 prime UTR NM_001406666.1:c.897T>A NP_001393595.1:p.Tyr299Ter nonsense NM_001406669.1:c.-572T>A 5 prime UTR NM_001406672.1:c.792+1813T>A intron variant NM_001406674.1:c.897T>A NP_001393603.1:p.Tyr299Ter nonsense NR_176230.1:n.933T>A non-coding transcript variant NR_176231.1:n.933T>A non-coding transcript variant NR_176232.1:n.933T>A non-coding transcript variant NR_176234.1:n.933T>A non-coding transcript variant NR_176235.1:n.933T>A non-coding transcript variant NR_176236.1:n.933T>A non-coding transcript variant NR_176237.1:n.933T>A non-coding transcript variant NR_176238.1:n.933T>A non-coding transcript variant NR_176239.1:n.933T>A non-coding transcript variant NR_176240.1:n.933T>A non-coding transcript variant NR_176241.1:n.933T>A non-coding transcript variant NR_176242.1:n.933T>A non-coding transcript variant NR_176244.1:n.933T>A non-coding transcript variant NR_176245.1:n.933T>A non-coding transcript variant NR_176246.1:n.933T>A non-coding transcript variant NR_176247.1:n.933T>A non-coding transcript variant NR_176248.1:n.933T>A non-coding transcript variant NR_176249.1:n.933T>A non-coding transcript variant NC_000002.12:g.47414373T>A NC_000002.11:g.47641512T>A NG_007110.2:g.16250T>A LRG_218:g.16250T>A LRG_218t1:c.897T>A LRG_218p1:p.Tyr299Ter - Protein change
- Y159*, Y279*, Y233*, Y288*, Y299*
- Other names
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- Canonical SPDI
- NC_000002.12:47414372:T: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 |
7402 | 7564 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
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Jul 28, 2023 | RCV003350730.2 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jul 28, 2023 | RCV003455811.1 | |
| Pathogenic (1) |
criteria provided, single submitter
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Nov 7, 2023 | RCV003594656.2 |
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. |
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Pathogenic
(Jul 28, 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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Myriad Genetics, Inc.
Accession: SCV004187862.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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Pathogenic
(Nov 07, 2023)
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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: SCV004292547.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr299*) in the MSH2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Tyr299*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28577310). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 28, 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: SCV004055872.2
First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024 |
Comment:
The p.Y299* pathogenic mutation (also known as c.897T>A), located in coding exon 5 of the MSH2 gene, results from a T to A substitution at … (more)
The p.Y299* pathogenic mutation (also known as c.897T>A), located in coding exon 5 of the MSH2 gene, results from a T to A substitution at nucleotide position 897. This changes the amino acid from a tyrosine to a stop codon within coding exon 5. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Tyr299*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28577310). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Y299* pathogenic mutation (also known as c.897T>A), located in coding exon 5 of the MSH2 gene, results from a T to A substitution at nucleotide position 897. This changes the amino acid from a tyrosine to a stop codon within coding exon 5. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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 variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
This sequence change creates a premature translational stop signal (p.Tyr299*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28577310). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Y299* pathogenic mutation (also known as c.897T>A), located in coding exon 5 of the MSH2 gene, results from a T to A substitution at nucleotide position 897. This changes the amino acid from a tyrosine to a stop codon within coding exon 5. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Elucidating the molecular basis of MSH2-deficient tumors by combined germline and somatic analysis. | Vargas-Parra GM | International journal of cancer | 2017 | PMID: 28577310 |
| 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 |
| Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. | Mangold E | International journal of cancer | 2005 | PMID: 15849733 |
Text-mined citations for this variant ...
HelpRecord last updated Sep 30, 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.