ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.142G>T (p.Glu48Ter)
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.142G>T (p.Glu48Ter)
Variation ID: 90662 Accession: VCV000090662.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47403333 (GRCh38) [ NCBI UCSC ] 2: 47630472 (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.142G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Glu48Ter nonsense NM_001258281.1:c.-30-27G>T intron variant NC_000002.12:g.47403333G>T NC_000002.11:g.47630472G>T NG_007110.2:g.5210G>T LRG_218:g.5210G>T LRG_218t1:c.142G>T LRG_218p1:p.Glu48Ter - Protein change
- E48*
- Other names
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- Canonical SPDI
- NC_000002.12:47403332:G:T
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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.
The Genome Aggregation Database (gnomAD) 0.00000
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 |
7207 | 7355 |
Conditions - Germline
Condition
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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
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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 | RCV000076158.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 26, 2016 | RCV000506167.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 3, 2022 | RCV000582377.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 4, 2023 | RCV000537461.6 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 7, 2023 | RCV000662482.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 21, 2022 | RCV001011543.2 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001354006.1 |
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
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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
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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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: SCV000107174.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comment:
Coding sequence variation introducing premature termination codon
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Pathogenic
(Jan 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: SCV001171876.3
First in ClinVar: Mar 16, 2020 Last updated: Nov 29, 2022 |
Comment:
The p.E48* pathogenic mutation (also known as c.142G>T), located in coding exon 1 of the MSH2 gene, results from a G to T substitution at … (more)
The p.E48* pathogenic mutation (also known as c.142G>T), located in coding exon 1 of the MSH2 gene, results from a G to T substitution at nucleotide position 142. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with MSH2-related disease (Ambry internal data). This mutation has been identified in numerous Lynch syndrome families to date (Tang R et al. Clin. Genet., 2009 Apr;75:334-45; Berends MJ et al. Int. J. Cancer, 2001 May;92:398-403; Sjursen W et al. J. Med. Genet., 2010 Sep;47:579-85; Zahary MN et al. World J. Gastroenterol., 2012 Feb;18:814-20). 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
(Jun 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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Baylor Genetics
Accession: SCV004194556.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Nov 26, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604262.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(Dec 31, 2020)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000691895.2
First in ClinVar: Feb 19, 2018 Last updated: Jun 02, 2021 |
Comment:
PVS1, PM2, PP5
Number of individuals with the variant: 1
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Pathogenic
(Mar 23, 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: SCV004018413.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 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
(Jun 04, 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: SCV000625261.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 19419416, 20587412, 22371642). For these reasons, this variant has been classified … (more)
This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 19419416, 20587412, 22371642). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90662). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu48*) 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
(Oct 10, 2017)
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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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Counsyl
Accession: SCV000784980.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Pathogenic
(Mar 03, 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: SCV002102635.2
First in ClinVar: Mar 12, 2022 Last updated: Mar 04, 2023 |
Comment:
Nonsense 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; Not … (more)
Nonsense 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; 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; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Pino 2009, Tang 2009, Sjursen 2010, Zahary 2012); This variant is associated with the following publications: (PMID: 26053027, 11291077, 19419416, 22371642, 20587412, 19324997, 31615790) (less)
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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: SCV000592452.2 First in ClinVar: Mar 24, 2015 Last updated: Apr 13, 2021 |
Comment:
The MSH2 p.Glu48X variant was identified in two reports, as a truncating mutation in endometrial cancer (Berends 2001), and as resulting in a loss of … (more)
The MSH2 p.Glu48X variant was identified in two reports, as a truncating mutation in endometrial cancer (Berends 2001), and as resulting in a loss of protein by immunohistochemistry in a patient with Lynch syndrome (Zahary 2012). The variant was also identified in dbSNP (ID: rs63750615) “With pathogenic allele”, “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database, and “the ClinVar database (classified as a pathogenic variant by an expert panel). The variant was not found in the following databases: NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, Clinvitae database, COSMIC, “MMR Gene Unclassified Variants Database”, Zhejiang Colon Cancer Database”, GeneInsight COGR database, and UMD. The p.Glu48X variant leads to a premature stop codon at position 48, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (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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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 |
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 |
Germline mutation analysis of MLH1 and MSH2 in Malaysian Lynch syndrome patients. | Zahary MN | World journal of gastroenterology | 2012 | PMID: 22371642 |
Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers. | Sjursen W | Journal of medical genetics | 2010 | PMID: 20587412 |
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 |
MLH1 and MSH2 protein expression as a pre-screening marker in hereditary and non-hereditary endometrial hyperplasia and cancer. | Berends MJ | International journal of cancer | 2001 | PMID: 11291077 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.142G%3ET | - | - | - | - |
Text-mined citations for rs63750615 ...
HelpRecord last updated Feb 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.