ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.387_388del (p.Gln130fs)
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.387_388del (p.Gln130fs)
Variation ID: 91089 Accession: VCV000091089.26
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 2p21 2: 47410108-47410109 (GRCh38) [ NCBI UCSC ] 2: 47637247-47637248 (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 28, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.387_388del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Gln130fs frameshift NM_000251.1:c.387_388delTC NM_000251.2:c.387_388delTC NM_001258281.1:c.189_190del NP_001245210.1:p.Gln64fs frameshift NC_000002.12:g.47410108TC[3] NC_000002.11:g.47637247TC[3] NG_007110.2:g.11985TC[3] LRG_218:g.11985TC[3] - Protein change
- Q130fs, Q64fs
- Other names
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- Canonical SPDI
- NC_000002.12:47410107:TCTCTCTC:TCTCTC
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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 | RCV000076591.14 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 6, 2021 | RCV000202145.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 14, 2022 | RCV000491648.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 17, 2023 | RCV000684791.14 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001353820.9 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2019 | RCV001250035.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 27, 2023 | RCV003452938.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 18, 2023 | RCV003313934.8 |
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
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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: SCV000107624.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comment:
Coding sequence variation resulting in a stop codon
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Pathogenic
(Sep 11, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601476.2
First in ClinVar: Sep 28, 2017 Last updated: Jan 01, 2022 |
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Pathogenic
(Apr 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002047951.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The MSH2 c.387_388delTC; p.Gln130ValfsTer2variant (rs63750924) is reported in the literature in several individuals affected with hereditary nonpolyposis colorectal cancer (Buerstedde 1995, Carter 2018, Lamberti 2006, … (more)
The MSH2 c.387_388delTC; p.Gln130ValfsTer2variant (rs63750924) is reported in the literature in several individuals affected with hereditary nonpolyposis colorectal cancer (Buerstedde 1995, Carter 2018, Lamberti 2006, Mangold 2005). This variant is also reported in ClinVar (Variation ID: 91089), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References Buerstedde et al. Detection of new mutations in six out of 10 Swiss HNPCC families by genomic sequencing of the hMSH2 and hMLH1 genes. J Med Genet. 1995 Nov;32(11):909-12. PMID: 8592341. Carter et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol 2018 Dec;151(3):481-488. PMID: 30322717. Lamberti C et al. Frequency of hereditary non-polyposis colorectal cancer among unselected patients with colorectal cancer in Germany. Digestion. 2006;74(1):58-67. PMID: 17095871. Mangold E et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2005 Sep 20;116(5):692-702. PMID: 15849733. (less)
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Pathogenic
(Jun 14, 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: SCV000580392.5
First in ClinVar: Jun 25, 2017 Last updated: Nov 29, 2022 |
Comment:
The c.387_388delTC pathogenic mutation, located in coding exon 3 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 387 to … (more)
The c.387_388delTC pathogenic mutation, located in coding exon 3 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 387 to 388, causing a translational frameshift with a predicted alternate stop codon (p.Q130Vfs*2). One study identified three individuals heterozygous for this mutation in a Swiss HNPCC family: an individual diagnosed with colon cancer at age 57, an individual diagnosed with rectal cancer at age 46 who was also reported to have several adenomas of the colon, and an individual diagnosed with cancers of the nasopharynx and colon at ages 24 and 43, respectively. Furthermore, one untested obligate carrier in the family was reported to have a glioblastoma multiforme consistent with Turcot's syndrome (Buerstedde JM et al. J. Med. Genet. 1995 Nov;32(11):909-12). An additional study identified this mutation in a single individual with demonstrated absence of MSH2 protein on immunohistochemistry and low microsatellite instability on tumor testing (Lamberti C et al. Digestion 2006;74:58-67). This alteration was reported somatically in a sebaceous neoplasm with absent MSH2 and MSH6 protein (Joly MO et al. Hum. Mutat. 2015 Mar;36:292-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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)
Number of individuals with the variant: 1
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Pathogenic
(Jul 27, 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: SCV004188005.1
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
(Jul 17, 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: SCV000255276.8
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91089). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91089). This variant is also known as 129delTC or c.388_389delTC. This premature translational stop signal has been observed in individuals with Lynch syndrome (PMID: 8592341, 10375096, 12658575, 15849733, 28514183). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln130Valfs*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). (less)
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Pathogenic
(Sep 16, 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: SCV000292615.10
First in ClinVar: Jul 24, 2016 Last updated: Sep 28, 2017 |
Comment:
This deletion of 2 nucleotides in MSH2 is denoted c.387_388delTC at the cDNA level and p.Gln130ValfsX2 (Q130VfsX2) at the protein level. The normal sequence, with … (more)
This deletion of 2 nucleotides in MSH2 is denoted c.387_388delTC at the cDNA level and p.Gln130ValfsX2 (Q130VfsX2) at the protein level. The normal sequence, with the bases that are deleted in braces, is TCTC[TC]AGTT. The deletion causes a frameshift, which changes a Glutamine to a Valine at codon 130, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 c.387_388delTC, also known as 129delTC or c.388_389delTC using alternative nomenclature, has been observed in several individuals with personal and/or family histories consistent with Lynch syndrome (Buerstedde 1995, Wagner 2003, Mangold 2005). We consider this variant to be pathogenic. (less)
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Pathogenic
(Jul 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004013450.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
A known pathogenic mutation was detected in the MSH2 gene (c.387_388delTC). This sequence change creates a premature translational stop signal (p.Gln130Valfs*2) in the MSH2 gene. … (more)
A known pathogenic mutation was detected in the MSH2 gene (c.387_388delTC). This sequence change creates a premature translational stop signal (p.Gln130Valfs*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 is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Lynch syndrome (PMID: 8592341, 10375096, 12658575, 15849733, 28514183). This variant is also known as 129delTC or c.388_389delTC. ClinVar contains an entry for this variant (Variation ID: 91089). For these reasons, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic mutations in the MSH2 gene are associated with hereditary nonpolyposis colorectal cancer syndrome, also known as Lynch syndrome. (less)
Age: 60-69 years
Sex: female
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000257188.2
First in ClinVar: Nov 20, 2015 Last updated: Sep 28, 2017 |
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Pathogenic
(Jul 01, 2019)
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no assertion criteria provided
Method: clinical testing
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Lynch-like syndrome
Affected status: yes
Allele origin:
somatic
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Constitutional Genetics Lab, Leon Berard Cancer Center
Accession: SCV001423960.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Carcinoma of colon
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592464.2 First in ClinVar: Oct 11, 2015 Last updated: Apr 13, 2021 |
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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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Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. | Espenschied CR | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28514183 |
Somatic MMR gene mutations as a cause for MSI-H sebaceous neoplasms in Muir-Torre syndrome-like patients. | Joly MO | Human mutation | 2015 | PMID: 25504677 |
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 |
Frequency of hereditary non-polyposis colorectal cancer among unselected patients with colorectal cancer in Germany. | Lamberti C | Digestion | 2006 | PMID: 17095871 |
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 |
Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. | Wagner A | American journal of human genetics | 2003 | PMID: 12658575 |
Influence of selection criteria on mutation detection in patients with hereditary nonpolyposis colorectal cancer. | Heinimann K | Cancer | 1999 | PMID: 10375096 |
Detection of new mutations in six out of 10 Swiss HNPCC families by genomic sequencing of the hMSH2 and hMLH1 genes. | Buerstedde JM | Journal of medical genetics | 1995 | PMID: 8592341 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.387_388del | - | - | - | - |
Text-mined citations for rs63750924 ...
HelpRecord last updated Apr 20, 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.