This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn596Glnfs*2) 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 has not been reported in the literature in individuals affected with MSH2-related conditions. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.1785dup (p.Asn596fs)
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.
Pathogenic
2
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.1785dup (p.Asn596fs)
Variation ID: 2089376 Accession: VCV002089376.3
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 2p21 2: 47475049-47475050 (GRCh38) [ NCBI UCSC ] 2: 47702188-47702189 (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 Feb 20, 2024 Aug 3, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000251.3:c.1785dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Asn596fs frameshift NM_001258281.1:c.1587dup NP_001245210.1:p.Asn530fs frameshift NM_001406631.1:c.1785dup NP_001393560.1:p.Asn596Glnfs frameshift NM_001406632.1:c.1785dup NP_001393561.1:p.Asn596Glnfs frameshift NM_001406633.1:c.1785dup NP_001393562.1:p.Asn596Glnfs frameshift NM_001406634.1:c.1785dup NP_001393563.1:p.Asn596Glnfs frameshift NM_001406635.1:c.1785dup NP_001393564.1:p.Asn596Glnfs frameshift NM_001406636.1:c.1752dup NP_001393565.1:p.Asn585Glnfs frameshift NM_001406637.1:c.1785dup NP_001393566.1:p.Asn596Glnfs frameshift NM_001406638.1:c.1824dup NP_001393567.1:p.Asn609Glnfs frameshift NM_001406639.1:c.1785dup NP_001393568.1:p.Asn596Glnfs frameshift NM_001406640.1:c.1785dup NP_001393569.1:p.Asn596Glnfs frameshift NM_001406641.1:c.1785dup NP_001393570.1:p.Asn596Glnfs frameshift NM_001406642.1:c.1785dup NP_001393571.1:p.Asn596Glnfs frameshift NM_001406643.1:c.1785dup NP_001393572.1:p.Asn596Glnfs frameshift NM_001406644.1:c.1785dup NP_001393573.1:p.Asn596Glnfs frameshift NM_001406645.1:c.1785dup NP_001393574.1:p.Asn596Glnfs frameshift NM_001406646.1:c.1785dup NP_001393575.1:p.Asn596Glnfs frameshift NM_001406647.1:c.1635dup NP_001393576.1:p.Asn546Glnfs frameshift NM_001406648.1:c.1785dup NP_001393577.1:p.Asn596Glnfs frameshift NM_001406649.1:c.1635dup NP_001393578.1:p.Asn546Glnfs frameshift NM_001406650.1:c.1635dup NP_001393579.1:p.Asn546Glnfs frameshift NM_001406651.1:c.1635dup NP_001393580.1:p.Asn546Glnfs frameshift NM_001406652.1:c.1635dup NP_001393581.1:p.Asn546Glnfs frameshift NM_001406653.1:c.1725dup NP_001393582.1:p.Asn576Glnfs frameshift NM_001406654.1:c.1365dup NP_001393583.1:p.Asn456Glnfs frameshift NM_001406655.1:c.1785dup NP_001393584.1:p.Asn596Glnfs frameshift NM_001406656.1:c.888dup NP_001393585.1:p.Asn297Glnfs frameshift NM_001406657.1:c.1687dup NP_001393586.1:p.Gln563Profs frameshift NM_001406658.1:c.429dup NP_001393587.1:p.Asn144Glnfs frameshift NM_001406659.1:c.429dup NP_001393588.1:p.Asn144Glnfs frameshift NM_001406660.1:c.429dup NP_001393589.1:p.Asn144Glnfs frameshift NM_001406661.1:c.429dup NP_001393590.1:p.Asn144Glnfs frameshift NM_001406662.1:c.429dup NP_001393591.1:p.Asn144Glnfs frameshift NM_001406669.1:c.429dup NP_001393598.1:p.Asn144Glnfs frameshift NM_001406674.1:c.1785dup NP_001393603.1:p.Asn596Glnfs frameshift NR_176230.1:n.1821dup NR_176231.1:n.1821dup NR_176232.1:n.1821dup NR_176233.1:n.1663dup NR_176234.1:n.1821dup NR_176235.1:n.1821dup NR_176236.1:n.1821dup NR_176237.1:n.1821dup NR_176238.1:n.1954dup NR_176239.1:n.1821dup NR_176240.1:n.1821dup NR_176241.1:n.1821dup NR_176242.1:n.1821dup NR_176243.1:n.1671dup NR_176244.1:n.1821dup NR_176245.1:n.1821dup NR_176246.1:n.1821dup NR_176247.1:n.1821dup NR_176248.1:n.1821dup NR_176249.1:n.2051dup NR_176250.1:n.1561dup NC_000002.12:g.47475050dup NC_000002.11:g.47702189dup NG_007110.2:g.76927dup LRG_218:g.76927dup LRG_218t1:c.1785dup LRG_218p1:p.Asn596Glnfs - Protein change
- N530fs, N596fs
- Other names
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- Canonical SPDI
- NC_000002.12:47475049:C:CC
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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. |
|||
| 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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 24, 2022 | RCV003005521.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 3, 2023 | RCV003455656.1 |
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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Pathogenic
(Jan 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003303970.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn596Glnfs*2) in the MSH2 gene. … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn596Glnfs*2) 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 has not been reported in the literature in individuals affected with MSH2-related conditions. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Aug 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004186810.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
|
Comment:
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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 not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn596Glnfs*2) 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 has not been reported in the literature in individuals affected with MSH2-related conditions. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 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.