ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.2113del (p.Val705fs)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.2113del (p.Val705fs)
Variation ID: 1760 Accession: VCV000001760.25
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 2p21 2: 47476474 (GRCh38) [ NCBI UCSC ] 2: 47703613 (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 Apr 4, 2013 Jun 9, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.2113del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Val705fs frameshift NM_000251.2:c.2113delG frameshift NM_001258281.1:c.1915del NP_001245210.1:p.Val639fs frameshift NC_000002.12:g.47476474del NC_000002.11:g.47703613del NG_007110.2:g.78351del LRG_218:g.78351del - Protein change
- V639fs
- Other names
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- Canonical SPDI
- NC_000002.12:47476473: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 |
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
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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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Pathogenic (2) |
criteria provided, single submitter
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Aug 7, 2023 | RCV000001830.4 | |
Pathogenic (1) |
reviewed by expert panel
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Sep 5, 2013 | RCV000030250.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 18, 2022 | RCV000223638.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 27, 2024 | RCV000791368.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 25, 2022 | RCV000482957.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 15, 2019 | RCV001175339.1 |
Submissions - Germline
Classification
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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: SCV000107421.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
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Comment:
Coding sequence variation introducing premature termination codon
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Pathogenic
(Jul 15, 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: SCV000052917.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MSH2 c.2113delG (p.Val705TrpfsX5) 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.2113delG (p.Val705TrpfsX5) 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 251476 control chromosomes. c.2113delG has been reported in the literature in multiple individuals affected with Lynch Syndrome (Moslein_1996, Lin_1999, Hegde_2005, Nilbert_2009, Coolbaugh-Murphy_2010). 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 25, 2022)
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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: SCV000568634.5
First in ClinVar: Apr 27, 2017 Last updated: Dec 03, 2022 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene, and segregates with disease in many affected individuals (Jeon et al. 1996; Moslein et al., 1996; Lin et al., 1999; Domingo et al., 2004; Hegde et al., 2005; Nilbert et al., 2009; Coolbaugh-Murphy et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 20052760, 15342696, 29238914, 16237223, 10080150, 8872463, 18566915, 8723682, 30787465) (less)
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Pathogenic
(Aug 07, 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: SCV004188027.1
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.
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Pathogenic
(Nov 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601455.3
First in ClinVar: Apr 27, 2017 Last updated: Jan 06, 2024 |
Comment:
This frameshift variant alters the translational reading frame of the MSH2 mRNA and causes the premature termination of MSH2 protein synthesis. This variant has not … (more)
This frameshift variant alters the translational reading frame of the MSH2 mRNA and causes the premature termination of MSH2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with hereditary nonpolyposis colorectal cancer (HNPCC) (PMID: 8723682 (2996), 8872463 (1996), 10080150 (1999), 15342696 (2004), 16237223 (2005), 20052760 (2010)). It has also been reported in individuals with Lynch Syndrome (PMID: 18566915 (2009), 29238914 (2018)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Oct 18, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001347251.3
First in ClinVar: Mar 25, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 1 nucleotide in exon 13 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide in exon 13 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals and families affected with Lynch syndrome (PMID: 8723682, 8872463, 10080150, 18566915, 20052760, 29238914). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 26, 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: SCV000278375.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The c.2113delG pathogenic mutation, located in coding exon 13 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 2113, causing … (more)
The c.2113delG pathogenic mutation, located in coding exon 13 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 2113, causing a translational frameshift with a predicted alternate stop codon (p.V705Wfs*5). This mutation has been detected in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several with family histories meeting Amsterdam criteria (Jeon HM et al. Hum. Mutat., 1996;7:327-33; Moslein G et al. Hum Mol Genet, 1996 Sep;5:1245-52)(Lin X et al. Dig. Dis. Sci., 1999 Mar;44:553-9; Domingo E et al. J Med Genet, 2004 Sep;41:664-8; Nilbert M et al. Fam Cancer, 2009 Jun;8:75-83; Coolbaugh-Murphy MI et al. Hum Mutat, 2010 Mar;31:317-24; Cloyd JM et al. J Gastrointest Cancer, 2018 Mar;49:93-96). 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
(Nov 02, 2020)
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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: SCV002534447.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH2 c.2113delG (p.V705WfsX5) variant has been reported in at least two individuals with Lynch syndrome (PMID: 18566915, 29238914). This variant causes a frameshift at … (more)
The MSH2 c.2113delG (p.V705WfsX5) variant has been reported in at least two individuals with Lynch syndrome (PMID: 18566915, 29238914). This variant causes a frameshift at amino acid 705 that results in premature termination 5 amino acids downstream. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). This variant is not reported in the population database Genome Aggregation Database (PMID: 27535533). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Jan 27, 2024)
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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: SCV000548168.8
First in ClinVar: Mar 24, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Val705Trpfs*5) 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.Val705Trpfs*5) 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 Lynch syndrome and Lynch syndrome-related cancers (PMID: 8723682, 8872463, 18566915, 20052760). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1760). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 1996)
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no assertion criteria provided
Method: literature only
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LYNCH SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021986.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
In 2 apparently unrelated families with familial nonpolyposis colon cancer type 1 (LYNCH1; 120435), Jeon et al. (1996) found the same mutation in exon 13 … (more)
In 2 apparently unrelated families with familial nonpolyposis colon cancer type 1 (LYNCH1; 120435), Jeon et al. (1996) found the same mutation in exon 13 of the MSH2 gene: deletion of a single nucleotide from codon 705, changing TGT to TT. Exon 13 of the MSH2 gene was chosen for screening because it is in the middle of the most conserved region of the gene. The 2 families did not fulfill the strict Amsterdam criteria for HNPCC because each had an unaffected individual over the age of 50 with the mutation. (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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Clinical and Genetic Implications of DNA Mismatch Repair Deficiency in Biliary Tract Cancers Associated with Lynch Syndrome. | Cloyd JM | Journal of gastrointestinal cancer | 2018 | PMID: 29238914 |
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 |
Microsatellite instability in the peripheral blood leukocytes of HNPCC patients. | Coolbaugh-Murphy MI | Human mutation | 2010 | PMID: 20052760 |
Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. | Nilbert M | Familial cancer | 2009 | PMID: 18566915 |
Assay validation for identification of hereditary nonpolyposis colon cancer-causing mutations in mismatch repair genes MLH1, MSH2, and MSH6. | Hegde M | The Journal of molecular diagnostics : JMD | 2005 | PMID: 16237223 |
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 |
BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. | Domingo E | Journal of medical genetics | 2004 | PMID: 15342696 |
Reduction in hMSH2 mRNA levels by premature translation termination: implications for mutation screening in hereditary nonpolyposis colorectal cancer. | Lin X | Digestive diseases and sciences | 1999 | PMID: 10080150 |
Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer. | Moslein G | Human molecular genetics | 1996 | PMID: 8872463 |
Mutation of the hMSH2 gene in two families with hereditary nonpolyposis colorectal cancer. | Jeon HM | Human mutation | 1996 | PMID: 8723682 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.2113del | - | - | - | - |
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Text-mined citations for rs63749811 ...
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.