ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.388_389del (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.388_389del (p.Gln130fs)
Variation ID: 91090 Accession: VCV000091090.29
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 2p21 2: 47410115-47410116 (GRCh38) [ NCBI UCSC ] 2: 47637254-47637255 (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 Feb 26, 2014 Feb 14, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.388_389del 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.388_389delCA NM_000251.2:c.388_389delCA frameshift NM_001258281.1:c.190_191del NP_001245210.1:p.Gln64fs frameshift NC_000002.12:g.47410115_47410116del NC_000002.11:g.47637254_47637255del NG_007110.2:g.11992_11993del LRG_218:g.11992_11993del - Protein change
- Q64fs
- Other names
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- Canonical SPDI
- NC_000002.12:47410114:CA:
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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 (2) |
reviewed by expert panel
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Sep 5, 2013 | RCV000076592.6 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 27, 2023 | RCV000087058.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 17, 2023 | RCV000163755.11 | |
Pathogenic (3) |
criteria provided, single submitter
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Jul 1, 2019 | RCV000235890.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 29, 2023 | RCV000816977.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 22, 2022 | RCV003137613.3 | |
Pathogenic (1) |
criteria provided, single submitter
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May 2, 2023 | RCV003390772.4 |
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
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: SCV000107625.3
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
(May 10, 2018)
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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: SCV000917697.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: MSH2 c.388_389delCA (p.Gln130ValfsX2) 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.388_389delCA (p.Gln130ValfsX2) 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 (eg. c.528_529delTG, p.Cys176X; c.704_705delAA, p.Lys235fsX20). The variant was absent in 121404 control chromosomes. c.388_389delCA has been reported in the literature in multiple individuals affected with Lynch Syndrome. The variant was reported as a founder mutation in Portuguese Lynch syndrome families (Pinheiro_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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
(Oct 21, 2021)
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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: SCV000214332.7
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The c.388_389delCA pathogenic mutation, located in coding exon 3 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 388 to … (more)
The c.388_389delCA pathogenic mutation, located in coding exon 3 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 388 to 389, causing a translational frameshift with a predicted alternate stop codon (p.Q130Vfs*2). This alteration has been detected in several Lynch Syndrome families (Mangold E et al. Int J Cancer. 2005 Sep 20;116(5):692-702; Walsh MD et al. Mod Pathol. 2012 May;25(5):722-30; Naseem H et al. Clin Genet. 2006 Nov;70(5):388-95; Maia S et al. Fam. Cancer 2016 Jan; 15(1):111-21). Additionally, this alteration has been identified multiple individuals with MSI-H colorectal cancer (CRC) tumors lacking MSH2 on IHC (Vaccaro CA et al. Dis Colon Rectum. 2007 Oct;50(10):1604-11; Barnetson RA et al. N Engl J Med. 2006 Jun 29; 354(26):2751-63) and in an individual diagnosed with gastric cancer (Vidal AF et al. BMC Cancer, 2021 Apr;21:363). This alteration was reported as a Portuguese founder mutation after it was detected in 16 unrelated Portuguese HNPCC families that met either Amsterdam or Bethesda criteria (Pinheiro M et al. Clin Genet. 2013 Sep;84(3):244-50). 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
(May 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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MSH2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004111545.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MSH2 c.388_389delCA variant is predicted to result in a frameshift and premature protein termination (p.Gln130Valfs*2). This variant was reported in multiple individuals/families with hereditary … (more)
The MSH2 c.388_389delCA variant is predicted to result in a frameshift and premature protein termination (p.Gln130Valfs*2). This variant was reported in multiple individuals/families with hereditary nonpolyposis colorectal cancer (Mangold et al. 2005. PubMed ID: 15849733, Pinheiro et al. 2013. PubMed ID: 23170986, Schneider et al. 2018. PubMed ID: 29575718, Soares et al. 2018. PubMed ID: 28932927). This variant has been establish as a founder mutation in Portuguese Lynch syndrome families (Pinheiro et al. 2013. PubMed ID: 23170986). This variant is classified as Pathogenic in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/91090/) and has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in MSH2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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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: SCV004188033.1
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
(Feb 08, 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: SCV004196868.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 29, 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: SCV000957509.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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 individual(s) with Lynch syndrome (PMID: 15849733, 23170986, 24344984). It is commonly reported in individuals of Portuguese ancestry (PMID: 15849733, 23170986, 24344984). ClinVar contains an entry for this variant (Variation ID: 91090). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 17, 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: SCV000690106.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 2 nucleotides in exon 3 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 2 nucleotides in exon 3 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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple individuals and families affected with Lynch syndrome-associated cancer (PMID: 15849733, 21642682, 22322191, 22480969, 23170986, 24344984, 28874130), and an individual from a family affected with Lynch syndrome who was affected with prostate cancer that demonstrated loss of MSH2 protein via immunohistochemistry analysis (PMID: 26289772). Haplotype analysis suggests that this is a founder mutation in the Portuguese population (PMID: 23170986). 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
(Jul 01, 2019)
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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: SCV000293505.10
First in ClinVar: Jul 24, 2016 Last updated: Jul 24, 2016 |
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; Not … (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; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28932927, 22480969, 16216036, 16341804, 24344984, 23170986, 26289772, 29575718, 15849733, 22322191, 21642682, 27007491, 33258288) (less)
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Pathogenic
(Dec 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Muir-Torré syndrome
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003806802.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated
Number of individuals with the variant: 1
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Pathogenic
(Sep 01, 2013)
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no assertion criteria provided
Method: literature only
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COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000119872.1
First in ClinVar: Feb 26, 2014 Last updated: Feb 26, 2014 |
Comment on evidence:
In affected members of 16 families from northern Portugal with HNPCC (120435), Pinheiro et al. (2013) identified a heterozygous 2-bp deletion (c.388_389del) in the MSH2 … (more)
In affected members of 16 families from northern Portugal with HNPCC (120435), Pinheiro et al. (2013) identified a heterozygous 2-bp deletion (c.388_389del) in the MSH2 gene. This mutation was found in 16% of 103 probands with HNPCC, and haplotype analysis indicated a relatively recent founder effect in this population. Haplotype analysis of 4 HNPCC1 families with this mutation from Germany, Scotland, England, and Argentina yielded different haplotype backgrounds, supporting the hypothesis that the mutation occurred de novo on multiple occasions. (less)
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Pathogenic
(-)
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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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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799737.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Pathogenic
(-)
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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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973455.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Lynch syndrome 1
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV002054066.2
First in ClinVar: Jan 08, 2022 Last updated: Oct 01, 2022 |
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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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Comprehensive analysis of germline mutations in northern Brazil: a panel of 16 genes for hereditary cancer-predisposing syndrome investigation. | Vidal AF | BMC cancer | 2021 | PMID: 33827469 |
Lynch Syndrome. | Adam MP | - | 2021 | PMID: 20301390 |
A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. | Rossi BM | BMC cancer | 2017 | PMID: 28874130 |
The role of germline mutations in the BRCA1/2 and mismatch repair genes in men ascertained for early-onset and/or familial prostate cancer. | Maia S | Familial cancer | 2016 | PMID: 26289772 |
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 |
Mutation spectrum in South American Lynch syndrome families. | Dominguez-Valentin M | Hereditary cancer in clinical practice | 2013 | PMID: 24344984 |
The MSH2 c.388_389del mutation shows a founder effect in Portuguese Lynch syndrome families. | Pinheiro M | Clinical genetics | 2013 | PMID: 23170986 |
Simplified identification of Lynch syndrome: a prospective, multicenter study. | Bonnet D | Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | 2012 | PMID: 22480969 |
Immunohistochemical testing of conventional adenomas for loss of expression of mismatch repair proteins in Lynch syndrome mutation carriers: a case series from the Australasian site of the colon cancer family registry. | Walsh MD | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2012 | PMID: 22322191 |
Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. | Bonadona V | JAMA | 2011 | PMID: 21642682 |
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 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.388_389del | - | - | - | - |
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Text-mined citations for rs63750704 ...
HelpRecord last updated Mar 11, 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.