ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.1035G>A (p.Trp345Ter)
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.1035G>A (p.Trp345Ter)
Variation ID: 90510 Accession: VCV000090510.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47416388 (GRCh38) [ NCBI UCSC ] 2: 47643527 (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 Mar 24, 2015 Feb 14, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.1035G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Trp345Ter nonsense NM_001258281.1:c.837G>A NP_001245210.1:p.Trp279Ter nonsense NC_000002.12:g.47416388G>A NC_000002.11:g.47643527G>A NG_007110.2:g.18265G>A LRG_218:g.18265G>A LRG_218t1:c.1035G>A LRG_218p1:p.Trp345Ter - Protein change
- W345*, W279*
- Other names
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- Canonical SPDI
- NC_000002.12:47416387: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
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The frequency of the allele represented by this VCV record.
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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 |
7262 | 7411 |
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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Pathogenic (1) |
reviewed by expert panel
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Sep 5, 2013 | RCV000076005.3 | |
Pathogenic (2) |
criteria provided, single submitter
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Apr 23, 2018 | RCV000202230.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2023 | RCV000492045.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2023 | RCV001258035.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 17, 2019 | RCV001193248.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 11, 2022 | RCV001854313.3 |
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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Pathogenic
(Sep 05, 2013)
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reviewed by expert panel
Method: research
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Lynch Syndrome
Affected status: unknown
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107016.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comment:
Coding sequence variant introducing a premature termination codon
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Pathogenic
(Jun 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361976.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MSH2 c.1035G>A (p.Trp345X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: MSH2 c.1035G>A (p.Trp345X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251438 control chromosomes. c.1035G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome or related cancer (Leon_2004, Roberts_2014, Kamiza_2015, Mu_2016, Vargas-Parra_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 21, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary non-polyposis colorectal cancer, type 1
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434863.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The c.1035G>A (p.Trp345*) variant in the MSH2 gene is predicted to introduce a premature translational termination codon. This variant has been reported in multiple individuals … (more)
The c.1035G>A (p.Trp345*) variant in the MSH2 gene is predicted to introduce a premature translational termination codon. This variant has been reported in multiple individuals with Lynch associated tumor (PMID 14970868, 15713769, 19419416, 28577310). Microsatellite instability (PMID 14970868) or MSH2 loss (PMID 15713769, 28577310) were observed in some of the tumors. This variant has never been observed in general population databases. Therefore, we classify this c.1035G>A (p.Trp345*) variant in the MSH2 gene as pathogenic. (less)
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Pathogenic
(Mar 30, 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: SCV000580470.6
First in ClinVar: Jun 25, 2017 Last updated: Jul 08, 2023 |
Comment:
The p.W345* pathogenic mutation (also known as c.1035G>A), located in coding exon 6 of the MSH2 gene, results from a G to A substitution at … (more)
The p.W345* pathogenic mutation (also known as c.1035G>A), located in coding exon 6 of the MSH2 gene, results from a G to A substitution at nucleotide position 1035. This changes the amino acid from a tryptophan to a stop codon within coding exon 6. This alteration has been reported in multiple individuals with personal and/or family histories consistent with Lynch syndrome (Ponz de Leon M et al, Br. J. Cancer 2004 Feb; 90(4):882-7; Tang R, Clin. Genet. 2009 Apr; 75(4):334-45). In addition, an alteration resulting in the same amino acid change and stop codon, p.W345* (c.1034G>A) has been reported in a HNPCC-like family with loss of expression of MSH2 on IHC (Casey G et al, JAMA 2005 Feb; 293(7):799-809). in addition to the clinical data presented in the literature, 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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Pathogenic
(Jul 31, 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: SCV004187948.1
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
(Apr 23, 2018)
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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: SCV000779393.2
First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015 |
Comment:
This variant is denoted MSH2 c.1035G>A at the cDNA level and p.Trp345Ter (W345X) at the protein level. The substitution creates a nonsense variant, which changes … (more)
This variant is denoted MSH2 c.1035G>A at the cDNA level and p.Trp345Ter (W345X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with Lynch syndrome (Ponz de Leon 2004, Tang 2009, Vargas-Parra 2017) and is considered pathogenic. (less)
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Pathogenic
(Feb 11, 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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Invitae
Accession: SCV002236755.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90510). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90510). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 14970868, 26053027). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp345*) 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). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000257120.1
First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015 |
Number of individuals with the variant: 1
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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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Elucidating the molecular basis of MSH2-deficient tumors by combined germline and somatic analysis. | Vargas-Parra GM | International journal of cancer | 2017 | PMID: 28577310 |
Hereditary cancer syndromes in Latino populations: genetic characterization and surveillance guidelines. | Cruz-Correa M | Hereditary cancer in clinical practice | 2017 | PMID: 28127413 |
Sanger Confirmation Is Required to Achieve Optimal Sensitivity and Specificity in Next-Generation Sequencing Panel Testing. | Mu W | The Journal of molecular diagnostics : JMD | 2016 | PMID: 27720647 |
Risk Factors Associated with Colorectal Cancer in a Subset of Patients with Mutations in MLH1 and MSH2 in Taiwan Fulfilling the Amsterdam II Criteria for Lynch Syndrome. | Kamiza AB | PloS one | 2015 | PMID: 26053027 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
A clinical scoring system to identify patients with sebaceous neoplasms at risk for the Muir-Torre variant of Lynch syndrome. | Roberts ME | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24603434 |
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 |
Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: characterization of a founder genomic mutation in the MLH1 gene. | Tang R | Clinical genetics | 2009 | PMID: 19419416 |
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 |
Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. | Casey G | JAMA | 2005 | PMID: 15713769 |
Genetic testing among high-risk individuals in families with hereditary nonpolyposis colorectal cancer. | Ponz de Leon M | British journal of cancer | 2004 | PMID: 14970868 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.1035G%3EA | - | - | - | - |
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Text-mined citations for rs63750396 ...
HelpRecord last updated Feb 14, 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.