ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.1A>G (p.Met1Val)
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.1A>G (p.Met1Val)
Variation ID: 90833 Accession: VCV000090833.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47403192 (GRCh38) [ NCBI UCSC ] 2: 47630331 (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 20, 2024 Jun 21, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.1A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Met1Val missense initiator codon variant NM_001258281.1:c.-31+17A>G intron variant NC_000002.12:g.47403192A>G NC_000002.11:g.47630331A>G NG_007110.2:g.5069A>G LRG_218:g.5069A>G LRG_218t1:c.1A>G LRG_218p1:p.Met1Val - Protein change
- M1V
- Other names
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- Canonical SPDI
- NC_000002.12:47403191: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.
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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 |
7200 | 7352 |
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000172811.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Sep 25, 2023 | RCV000165763.8 | |
Uncertain significance (2) |
reviewed by expert panel
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Jun 21, 2019 | RCV000076335.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 6, 2023 | RCV000560664.9 | |
Uncertain significance (3) |
criteria provided, single submitter
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May 20, 2015 | RCV000235433.6 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2021 | RCV003162494.2 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
(Jun 21, 2019)
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reviewed by expert panel
Method: curation
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Lynch syndrome
Affected status: yes
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107359.4
First in ClinVar: Dec 19, 2013 Last updated: Sep 03, 2023 |
Comment:
Insufficient evidence
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Uncertain significance
(Sep 25, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001349267.4
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant alters the translation initiation codon methionine of the MSH2 protein. To our knowledge, functional studies have not been reported for this variant, and … (more)
This variant alters the translation initiation codon methionine of the MSH2 protein. To our knowledge, functional studies have not been reported for this variant, and it is unknown whether this variant impacts the full length protein expression or results in the use of alternate downstream methionine for translation initiation (PMID: 21837758). This variant has been reported in trans with a pathogenic MSH2 variant in two siblings who did not present with constitutional mismatch repair deficiency syndrome, but were affected with multiple, early-onset Lynch syndrome-related cancers (PMID: 18781192). Their phenotypes were more suggestive of a monoallelic mutation, and tumors showed microsatellite instability in the presence of MLH1, PMS2, MSH2 and MSH6 proteins (PMID: 18781192). This variant was found in the probands' unaffected mother in her 80s, who lacked family history of Lynch syndrome-associated cancers. This variant has been reported in an individual affected with pancreatic cancer, who also carried a pathogenic variant in the CDKN2A gene (PMID: 27449771). This variant has been identified in 3/214858 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 06, 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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Invitae
Accession: SCV000625336.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects the initiator methionine of the MSH2 mRNA. The next in-frame methionine is located at codon 26. It is unclear whether it … (more)
This sequence change affects the initiator methionine of the MSH2 mRNA. The next in-frame methionine is located at codon 26. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 26 has the potential to rescue this variant. This variant is present in population databases (rs267607911, gnomAD 0.006%). Disruption of the initiator codon has been observed in individual(s) with MSH2-related cancers (PMID: 9718327, 10874307, 18033691, 18781192, 21837758, 23047549, 25639900, 27449771, 28944238). Disruption of the initiator codon has been observed on the opposite chromosome (in trans) from a pathogenic variant in MSH2 in an individual who was not affected with recessive MSH2-related conditions (PMID: 18781192, 25639900). This suggests that this variant may not be disease-causing. ClinVar contains an entry for this variant (Variation ID: 90833). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Reports on variants that affect the MSH2 initiator codon, c.1A>C and c.1A>T, indicate that Met26 may serve as an alternate initiator codon (PMID: 21837758, 9718327, 18781192). An experimental study of a recombinant MSH2 protein lacking the first 25 amino acid residues has shown that the truncated protein remains partially functional (PMID: 21837758). The clinical significance of these findings is unknown. 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
(Oct 30, 2014)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome I
Affected status: unknown
Allele origin:
germline
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Pathway Genomics
Accession: SCV000223777.2
First in ClinVar: Jun 04, 2015 Last updated: Sep 03, 2023 |
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Uncertain significance
(May 20, 2015)
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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: SCV000292892.11
First in ClinVar: Jul 24, 2016 Last updated: Sep 03, 2023 |
Comment:
The c.1A>G variant in the MSH2 gene results in the loss of the initiator Methionine codon, and the resultant protein would be described as ?p.Met1?? … (more)
The c.1A>G variant in the MSH2 gene results in the loss of the initiator Methionine codon, and the resultant protein would be described as ?p.Met1?? to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. This variant was reported in two siblings who were compound heterozygotes for MSH2 c.1A>G and a known pathogenic MSH2 deletion in the absence of constitutional mismatch repair-deficiency (CMMR-D) syndrome, but who did display a phenotype more severe than classical Lynch syndrome, leading the authors to suggest that a variant in this start codon may be associated with reduced penetrance (Kets 2009). Additionally, the unaffected mother was found to only harbor the MSH2 c.1A>G variant, which in combination with the lack of Lynch syndrome-associated cancers in her family, further supports a less severe phenotype than classic Lynch syndrome. Corresponding tumor studies from the siblings showed weak MSH2 staining and microsatellite instability, suggesting that this variant confers reduced, but not complete, loss of protein activity. Another initiation codon variant, MSH2 c.1A>C, has also been suggested to be associated with an attenuated Lynch syndrome phenotype. This variant demonstrated impaired, but not complete loss of protein activity, and has been shown to produce multiple protein products, including both full-length and truncated MSH2 protein (Barnetson 2006, Barnetson 2008, Cyr 2012). Thus, the effects of these two start codon missense variants appear to be similar. There is some published evidence that this variant increases the risk of Lynch-related cancers (colon, endometrial, etc.) in the heterozygous state. However, based on internal data acquired from multiple observations of this variant and MSH2 c.1A>C in individuals without histories suggestive of Lynch syndrome, the cancer risks associated with this variant may be lower than what is expected for typical Lynch syndrome. Based on currently available data the cancer risks associated with MSH2 c.1A>G are not well understood, thus we consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(May 28, 2019)
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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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Mendelics
Accession: SCV001135686.2
First in ClinVar: Jan 13, 2020 Last updated: Sep 03, 2023 |
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Uncertain significance
(Sep 21, 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: SCV000216508.7
First in ClinVar: Mar 24, 2015 Last updated: Sep 03, 2023 |
Comment:
The p.M1? variant (also known as c.1A>G) is located in coding exon 1 of the MSH2 gene and results from an A to G substitution … (more)
The p.M1? variant (also known as c.1A>G) is located in coding exon 1 of the MSH2 gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however there is an alternate in-frame methionine 25 amino acids from the initiation site and the significance of the N-terminus for this protein is not well established. This alteration has been reported in trans with a pathogenic MSH2 gross deletion in two siblings whose phenotypes were in the monoallelic HNPCC spectrum; however, microsatellite instability (MSI) and immunohistochemical (IHC) data were conflicting and the number of adenomas in one of the siblings was higher than expected (Kets CM, Eur. J. Hum. Genet. 2009 Feb; 17(2):159-64). This alteration has also been reported in one of 43 pancreatic cancer patients who also carried germline CDKN2A mutations (Yang XR et al. Hum. Genet., 2016 Nov;135:1241-1249). Alterations at the initiation codon of MSH2 have been identified in several cancer cohorts including ovarian cancer, early-onset colorectal cancer (diagnosed under age 30) and known or suspected Lynch syndrome cases; however, tumors do not consistently demonstrate a pattern of MSI and mismatch repair protein-deficient IHC staining (Farrington SM et al. Am. J. Hum. Genet. 1998 Sep 63(3):749-59; Otway R et al. Hum. Mutat. 2000;16(1):61-7; Barnetson RA et al. N. Engl. J. Med. 2006 Jun;354(26):2751-63; Barnetson RA et al. Hum. Mutat. 2008 Mar;29(3):367-74; Pal T et al. Br. J. Cancer. 2012 Nov;107(10):1783-90; Desmond A et al. JAMA Oncol. 2015 Oct;1(7):943-51). Further, transfection of a similar alteration impacting the initiation codon of MSH2, c.1A>C, cDNA into an MSH2-null, human endometrial cancer cell line showed slight, but statistically significant decrease in repair of an exogenous mismatched protein. This attenuated effect may be due to partial function of the truncated protein and/or expression of the full-length protein resulting from weak translation at the altered, non-AUG start codon, which was detected concomitantly with the truncated protein in this study (Cyr JL et al. Mol. Carcinog. 2012 Aug;51(8):647-58). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Jul 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000837809.3
First in ClinVar: Oct 10, 2018 Last updated: Sep 03, 2023 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001924767.2 First in ClinVar: Sep 24, 2021 Last updated: Sep 03, 2023 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955101.2 First in ClinVar: Oct 02, 2021 Last updated: Sep 03, 2023 |
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Pathogenic
(Jul 01, 2021)
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no assertion criteria provided
Method: research
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Gastric cancer
Affected status: unknown
Allele origin:
germline
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Laboratory for Genotyping Development, RIKEN
Accession: SCV002758533.2
First in ClinVar: Apr 15, 2023 Last updated: Sep 03, 2023 |
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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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Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
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 |
Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. | DeRycke MS | Molecular genetics & genomic medicine | 2017 | PMID: 28944238 |
Multiple rare variants in high-risk pancreatic cancer-related genes may increase risk for pancreatic cancer in a subset of patients with and without germline CDKN2A mutations. | Yang XR | Human genetics | 2016 | PMID: 27449771 |
Exceptions to the rule: case studies in the prediction of pathogenicity for genetic variants in hereditary cancer genes. | Rosenthal ET | Clinical genetics | 2015 | PMID: 25639900 |
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 |
The predicted truncation from a cancer-associated variant of the MSH2 initiation codon alters activity of the MSH2-MSH6 mismatch repair complex. | Cyr JL | Molecular carcinogenesis | 2012 | PMID: 21837758 |
Compound heterozygosity for two MSH2 mutations suggests mild consequences of the initiation codon variant c.1A>G of MSH2. | Kets CM | European journal of human genetics : EJHG | 2009 | PMID: 18781192 |
Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer. | Barnetson RA | Human mutation | 2008 | PMID: 18033691 |
Evaluation of enzymatic mutation detectiontrade mark in hereditary nonpolyposis colorectal cancer. | Otway R | Human mutation | 2000 | PMID: 10874307 |
Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls. | Farrington SM | American journal of human genetics | 1998 | PMID: 9718327 |
http://insight-group.org/variants/classifications | - | - | - | - |
http://www.insight-database.org/classifications/?gene=MSH2&variant=c.1A%3EG | - | - | - | - |
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Text-mined citations for rs267607911 ...
HelpRecord last updated Mar 17, 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.