Multifactorial likelihood analysis posterior probability >0.99. Variant causes in-frame splicing aberration which interrupts know functional domains
ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.942+3A>T
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Sep 2013 by
International …
for
Lynch Syndrome
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000251.3(MSH2):c.942+3A>T
Variation ID: 36580 Accession: VCV000036580.65
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47414421 (GRCh38) [ NCBI UCSC ] 2: 47641560 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 20, 2024 Sep 5, 2013 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000251.3:c.942+3A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001258281.1:c.744+3A>T intron variant NC_000002.12:g.47414421A>T NC_000002.11:g.47641560A>T NG_007110.2:g.16298A>T LRG_218:g.16298A>T LRG_218t1:c.942+3A>T - Protein change
- -
- Other names
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IVS5+3A>T
DEL EXON 5
IVS5DS, A-T, +3
- Canonical SPDI
- NC_000002.12:47414420:A: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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exon loss; Variation Ontology [ VariO:0381] PubMed: 8062247sequence variant affecting splice donor; Sequence Ontology [ SO:1000072]
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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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00072
The Genome Aggregation Database (gnomAD), exomes 0.00003
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7402 | 7564 | |
Conditions - Germline
| Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (10) |
criteria provided, conflicting classifications
|
Mar 26, 2024 | RCV000001844.20 | |
| Pathogenic (4) |
reviewed by expert panel
|
Sep 5, 2013 | RCV000030256.15 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 22, 2023 | RCV000115549.18 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Mar 25, 2024 | RCV000201997.37 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 22, 2024 | RCV000524424.10 | |
|
Lynch-like syndrome
|
Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2019 | RCV001249912.1 |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001353565.2 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 21, 2021 | RCV001579303.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 8, 2021 | RCV001731319.1 | |
|
MSH2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Aug 8, 2024 | RCV004734535.1 |
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
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
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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|---|---|---|---|---|---|
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Pathogenic
(Sep 05, 2013)
|
reviewed by expert panel
Method: research
|
Lynch Syndrome
Affected status: unknown
Allele origin:
germline
|
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107794.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
|
Comment:
Multifactorial likelihood analysis posterior probability >0.99. Variant causes in-frame splicing aberration which interrupts know functional domains
|
|
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Pathogenic
(Nov 17, 2015)
|
criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000487770.2
First in ClinVar: Oct 22, 2016 Last updated: Dec 24, 2022 |
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Pathogenic
(Jul 12, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601495.6
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
Comment:
The MSH2 c.942+3A>T variant has been reported in the published literature in several affected individuals with Lynch Syndrome-related cancers (PMIDs: 23329266 (2013), 22949379 (2013), 24323032 … (more)
The MSH2 c.942+3A>T variant has been reported in the published literature in several affected individuals with Lynch Syndrome-related cancers (PMIDs: 23329266 (2013), 22949379 (2013), 24323032 (2014), 25117503 (2014), 28874130 (2017), 35734982 (2022), and 36421850 (2022)). A functional study demonstrated that this variant alters normal splicing and results in exon 5 skipping (PMID: 16395668 (2006)). It has also been described as the most common recurrent de novo germline variant in a human mismatch repair gene (PMID: 10978353 (2000)), as well as the most common Lynch Syndrome variant in the world (PMIDs: 20682701 (2010)). The frequency of this variant in the general population, 0.000033 (1/30582 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper MSH2 mRNA splicing. Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004562878.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The MSH2 c.942+3A>T variant (rs193922376) is well-described in the literature to be associated with Lynch syndrome and colorectal cancer (Desai 2000, Lage 2004, Liu 1994, … (more)
The MSH2 c.942+3A>T variant (rs193922376) is well-described in the literature to be associated with Lynch syndrome and colorectal cancer (Desai 2000, Lage 2004, Liu 1994, Woods 2010, Mismatch Repair Genes Variant Database and references therein). This variant is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 36580). This is an intronic variant in a moderately conserved nucleotide, and RNA analyses indicate this variant weakens the canonical donor splice site of intron 5 and leads to exon 5 skipping (Auclair 2006, Liu 1994). Based on available information, this variant is considered to be pathogenic. References: Link to Mismatch Repair Genes Variant Database: http://www.med.mun.ca/mmrvariants/search_results.aspx Auclair J et al. Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. Hum Mutat. 2006 Feb;27(2):145-54. PMID: 16395668. Desai DC et al. Recurrent germline mutation in MSH2 arises frequently de novo. J Med Genet. 2000 Sep;37(9):646-52. PMID: 10978353. Lage PA et al. Association of colonic and endometrial carcinomas in Portuguese families with hereditary nonpolyposis colorectal carcinoma significantly increases the probability of detecting a pathogenic mutation in mismatch repair genes, primarily the MSH2 gene. Cancer. 2004 Jul 1;101(1):172-7. PMID: 15222003. Liu B et al. hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res. 1994 Sep 1;54(17):4590-4. PMID: 8062247. Woods MO et al. The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease. Gut. 2010 Oct;59(10):1369-77. PMID: 20682701. (less)
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Pathogenic
(Mar 09, 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
|
Ambry Genetics
Accession: SCV000185219.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.942+3A>T intronic pathogenic mutation results from an A to T substitution 3 nucleotides after coding exon 5 in the MSH2 gene. In one study, … (more)
The c.942+3A>T intronic pathogenic mutation results from an A to T substitution 3 nucleotides after coding exon 5 in the MSH2 gene. In one study, this mutation was found in eight unrelated Lynch syndrome families. Six of the eight families (75%) had one family member diagnosed with either a keratocanthoma or sebaceous adenoma associated with Muir-Torre syndrome, along with some combination of colon, uterine, and/or ureter transitional cell cancers in the family (South CD et al. J. Natl. Cancer Inst. 2008 Feb;100:277-81). This mutation was also reported in a German patient diagnosed with malignant fibrous histiocytoma (MFH) (Brieger A et al. Fam. Cancer. 2011 Sep;10:591-5). Authors of one study claim that this is the most common recurrent de novo germline mutation in a human mismatch repair gene, accounting for approximately 11% of all known pathogenic MSH2 gene mutations (Desai DC et al. J. Med. Genet. 2000 Sep;37:646-52). Multiple studies have demonstrated that this mutation results in an mRNA transcript lacking coding exon 5 (Casey G et al. JAMA. 2005 Feb;293:799-809; Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54; Arnold S et al. Hum. Mutat. 2009 May;30:757-70; Chong G et al. Hum. Mutat. 2009 Aug;30:E797-812). Of note, this mutation is also designated as IVS5+3A>T in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004196207.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
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Pathogenic
(Jul 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743207.1 First in ClinVar: Oct 22, 2016 Last updated: Oct 22, 2016 |
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Pathogenic
(Jan 30, 2019)
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criteria provided, single submitter
Method: research
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Lynch syndrome
Affected status: yes
Allele origin:
germline
|
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center
Accession: SCV000914299.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Number of individuals with the variant: 2
Geographic origin: Brazil
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Pathogenic
(Sep 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052923.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 30, 2021 |
Comment:
Variant summary: MSH2 c.942+3A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: MSH2 c.942+3A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5 prime splicing donor site; two predict the variant weakens a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Liu_1994). The variant allele was found at a frequency of 3.3e-05 in 30582 control chromosomes. c.942+3A>T has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Liu_1994, Thibodeau_1996, Chan_1999, Desai_2000, Green_2002, Win_2011). These data indicate that the variant is very likely to be associated with disease. Fourteen 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
(Mar 10, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002526774.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH2 c.942+3A>T variant has been reported in heterozygosity in numerous individuals and families with Lynch syndrome and Lynch-syndrome associated cancers (PMID: 8062247, 16395668, 21598002, … (more)
The MSH2 c.942+3A>T variant has been reported in heterozygosity in numerous individuals and families with Lynch syndrome and Lynch-syndrome associated cancers (PMID: 8062247, 16395668, 21598002, 22883484, 28874130, 29575718, 16203774). Functional studies have shown that this variant results in exon 5 skipping (PMID: 16395668, 8062247). This variant is a well-established pathogenic variant associated with Lynch syndrome (PMID: 8062247, 16395668, 21598002, 22883484, 28874130, 29575718, 16203774, 25025451). This variant was observed in 1/12862 chromosomes in the Non-Finnish European population, with 0 homozygotes, according to the Genome Aggregation Database (PMID: 32461654). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Mar 24, 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
|
Myriad Genetics, Inc.
Accession: SCV004018422.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8062247].
|
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Pathogenic
(Jan 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017564.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Feb 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000690146.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant causes an A to T nucleotide substitution at the +3 position of intron 5 of the MSH2 gene. RNA studies have shown this … (more)
This variant causes an A to T nucleotide substitution at the +3 position of intron 5 of the MSH2 gene. RNA studies have shown this variant caused skipping of exon 5 (r.793_942del) and in-frame deletion of 50 amino acids in the DNA binding domain (PMID: 8062247, 16395668, 19267393). This variant has been reported as a recurrent de novo mutation in individuals affected with Lynch syndrome-associated cancer in different ethnicities (PMID: 10978353). This variant has been reported in many individuals and families with Lynch syndrome or suspected Lynch syndrome worldwide (PMID: 8062247, 10413423, 10446963, 11920650, 12112654, 12362047, 15222003, 16203774, 16395668, 17312306, 18625694, 19130300, 19419416, 20682701, 21681552, 22883484), and shown to segregate with Lynch syndrome cancers in family studies (PMID: 19267393). This variant is considered to be a founder mutation in the Newfoundland population (PMID: 20682701). This variant has been identified in 1/30582 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Uncertain significance
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806138.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
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Pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004821994.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This variant causes an A to T nucleotide substitution at the +3 position of intron 5 of the MSH2 gene. RNA studies have shown this … (more)
This variant causes an A to T nucleotide substitution at the +3 position of intron 5 of the MSH2 gene. RNA studies have shown this variant caused skipping of exon 5 (r.793_942del) and in-frame deletion of 50 amino acids in the DNA binding domain (PMID: 8062247, 16395668, 19267393). This variant has been reported as a recurrent de novo mutation in individuals affected with Lynch syndrome-associated cancer in different ethnicities (PMID: 10978353). This variant has been reported in many individuals and families with Lynch syndrome or suspected Lynch syndrome worldwide (PMID: 8062247, 10413423, 10446963, 11920650, 12112654, 12362047, 15222003, 16203774, 16395668, 17312306, 18625694, 19130300, 19419416, 20682701, 21681552, 22883484), and shown to segregate with Lynch syndrome cancers in family studies (PMID: 19267393). This variant is considered to be a founder mutation in the Newfoundland population (PMID: 20682701). This variant has been identified in 1/30582 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 4
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Pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199171.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
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Pathogenic
(Sep 21, 2015)
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criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744270.1 First in ClinVar: Oct 22, 2016 Last updated: Oct 22, 2016 |
|
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Pathogenic
(Jul 25, 2013)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000110277.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
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Pathogenic
(Apr 12, 2018)
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criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428898.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Number of individuals with the variant: 1
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)
Accession: SCV002318379.2
First in ClinVar: Apr 02, 2022 Last updated: Sep 24, 2022 |
Observation 1:
Age: 60-69 years
Sex: male
Geographic origin: Algeria
Observation 2:
Age: 30-39 years
Sex: male
Geographic origin: Algeria
Observation 3:
Age: 20-29 years
Sex: female
Geographic origin: Algeria
Observation 4:
Age: 30-39 years
Sex: female
Geographic origin: Algeria
Observation 5:
Age: 40-49 years
Sex: female
Geographic origin: Algeria
|
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Pathogenic
(Apr 13, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149458.17
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
Originally reported to be a pathogenic founder variant in Newfoundland, but has since been hypothesized to be a mutational hotspot identified in individuals of varying … (more)
Originally reported to be a pathogenic founder variant in Newfoundland, but has since been hypothesized to be a mutational hotspot identified in individuals of varying ethnicities without a common haplotype identified (Desai 2000); Published functional studies demonstrate a damaging effect: skipping of exon 5 (Liu 1994, Auclair 2006); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Liu 1994, Froggatt 1999, Kurzawski 2005, Buchanan 2014, Rosty 2014, Harper 2016, Roth 2016, Ziada-Bouchaar 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 18270343, 10978353, 21598002, 8062247, 27064304, 26873718, 31857677, 25525159, 30702970, 29575718, 29665779, 30680046, 22883484, 25117503, 24323032, 23329266, 21642682, 23255516, 12362047, 19125127, 24603434, 19575290, 18809606, 25479140, 25345868, 10051005, 25648859, 25980754, 21056691, 22775459, 25110875, 20587412, 16395668, 22949379, 21636617, 27013479, 21681552, 26666765, 27468915, 26143115, 27601186, 27978560, 27357288, 27720647, 28243543, 19606495, 18566915, 28152038, 27713421, 28502729, 28514183, 26681312, 28873162, 28577310, 28874130, 29967423, 30093976, 31054147, 30553995, 25795746, 18460031, 31444830, 25025451, 32658311, 31615790, 33484353, 34178123, 31332305, 30875412, 30787465, 33726816) (less)
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Pathogenic
(Jan 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000257198.4
First in ClinVar: Nov 20, 2015 Last updated: Jan 26, 2024 |
Comment:
PP4, PP5, PM2, PS3, PS4_moderate
Number of individuals with the variant: 9
|
|
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Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000211911.14
First in ClinVar: Mar 03, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 5 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. … (more)
This sequence change falls in intron 5 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 8062247, 10978353, 15222003, 19419416, 20682701, 21681552, 22883484, 24310308). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36580). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 5, but is expected to preserve the integrity of the reading-frame (PMID: 8062247, 16395668; Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711430.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024 |
Comment:
The c.942+3A>T variant in MSH2 has been reported in >150 individuals with Lynch syndrome (LabCorp database, Woods 2010). This variant has been identified in 1/12862 … (more)
The c.942+3A>T variant in MSH2 has been reported in >150 individuals with Lynch syndrome (LabCorp database, Woods 2010). This variant has been identified in 1/12862 of European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). In vitro functional studies show that the c.942+3A>T variant leads to an in-frame deletion of exon 5 (Auclair 2006). In addition, it has been classified as Pathogenic on December 18, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107794.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon the predicted impact to the protein, low frequency in controls and presence in affected individuals. ACMG/AMP Criteria applied: PS4, PM2, PS3_Supporting, PVS1_Strong. (less)
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Pathogenic
(Jul 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033723.11
First in ClinVar: Sep 16, 2023 Last updated: Oct 20, 2024 |
Comment:
MSH2: PS3, PS4, PM2, PP1
Number of individuals with the variant: 2
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Pathogenic
(Sep 01, 2000)
|
no assertion criteria provided
Method: literature only
|
COLORECTAL CANCER, HEREDITARY, NONPOLYPOSIS, TYPE 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000021989.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Froggatt et al. (1999) reported an A-to-T transversion at nucleotide 943+3 of the MSH2 gene disrupting the 3-prime splice site of exon 5 and leading … (more)
Froggatt et al. (1999) reported an A-to-T transversion at nucleotide 943+3 of the MSH2 gene disrupting the 3-prime splice site of exon 5 and leading to deletion of this exon from the MSH2 mRNA. This mutation was originally identified in 3 of 29 North American HNPCC (HNPCC1; 120435) families (Liu et al., 1994) and had also been found in 4 of 52 English families and in 10 of 20 families from Newfoundland. Froggatt et al. (1999) stated that this was the most common MSH2 mutation reported to that time. To investigate the origin of this mutation in these families, Froggatt et al. (1999) performed haplotype analysis using microsatellite markers linked to MSH2. A common haplotype was identified in 8 of the Newfoundland families, suggesting a founder effect. Froggatt et al. (1999) calculated age-related risks of all, colorectal, endometrial, and ovarian cancers in 76 carriers of the nucleotide 943+3 A-to-T MSH2 mutation for all patients and for men and women separately. For both sexes combined, the penetrance at age 60 years for all cancers and colorectal cancers was 0.86 and 0.57, respectively. The risk of colorectal cancer was significantly higher (P = less than 0.01) in males than in females. For females there was a high risk of endometrial cancer (0.5 at age 60 years) and premenopausal ovarian cancer (0.2 at 50 years). In a note added in proof, Froggatt et al. (1999) reported that another 21 HNPCC families had been identified in Newfoundland, 1 of which carried the 943+3A-T mutation, raising the proportion of Newfoundland families with this mutation to 11 of 41 (27%). Three of these families were shown to have a common ancestor, and another common ancestor was found for an additional 2 families. Desai et al. (2000) studied 10 families from England, Italy, Hong Kong, and Japan with this mutation. Haplotype sharing was not apparent even within the European and the Asian kindreds. The authors concluded that the 943+3A-T mutation occurs de novo with relatively high frequency and hypothesized that it arises as a consequence of misalignment at replication or recombination caused by a repeat of 26 adenine residues, of which the mutated A is the first. (less)
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Pathogenic
(Aug 08, 2024)
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no assertion criteria provided
Method: clinical testing
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MSH2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000806051.2
First in ClinVar: Sep 13, 2018 Last updated: Oct 08, 2024 |
Comment:
The MSH2 c.942+3A>T variant is predicted to interfere with splicing. This variant is a documented causative variant (germline and somatic) for several types of cancers … (more)
The MSH2 c.942+3A>T variant is predicted to interfere with splicing. This variant is a documented causative variant (germline and somatic) for several types of cancers (e.g. cancers of bladder, colorectal, ovarian, sebaceous gland, prostate etc.) (Haraldsdottir et al. 2014. PubMed ID: 25194673; Susswein et al. 2016, Table S1, PubMed ID: 26681312; Dominguez-Valentin et al. 2016, PubMed ID: 27013479). Also, it is a recurrent pathogenic variant of nonpolyposis colorectal cancer (Desai et al. 2000, PubMed ID: 10978353) and reported as both a de novo and a familial variant and represents above 10% of all MSH2 positive cases (Mangold et al. 2005, PubMed ID: 15849733). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/36580). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jul 01, 2019)
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no assertion criteria provided
Method: clinical testing
|
Lynch-like syndrome
Affected status: yes
Allele origin:
somatic
|
Constitutional Genetics Lab, Leon Berard Cancer Center
Accession: SCV001423929.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Carcinoma of colon
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592480.2 First in ClinVar: Oct 11, 2015 Last updated: Apr 13, 2021 |
Comment:
The MSH2 c.942+3A>T variant was identified in 12 of 2642 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer, and was not identified … (more)
The MSH2 c.942+3A>T variant was identified in 12 of 2642 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer, and was not identified in 200 control chromosomes from healthy individuals (Auclair 2006, Brieger 2011, Canard 2012, Froggatt 1996, Grindedal 2009, Kurzawski 2002, Sheng 2008). The variant was also identified by our laboratory in 8 individuals with colorectal cancer. The variant was identified in dbSNP (ID: rs193922376) as “With Pathogenic allele”, Clinvitae database (as pathogenic), “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), ClinVar database (classified as pathogenic by InSight, Emory Genetics, Ambry genetics, Invitae, LabCorp, COGR, Mayo Clinic, GeneDx, OMIM) and UMD (111X with a “causal” classification). The c.942+3A>T variant is located at the donor splice site (or 3’ splice site of exon 5) but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. Furthermore, several population studies suggest the variant lead to an in-frame deletion of exon 5 and loss of MSH2 protein expression (Auclair 2006, Brieger 2011, Canard 2012, Kurzawski 2002). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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Pathogenic
(Aug 21, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Breast carcinoma
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001805837.1
First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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not provided
(-)
|
no classification provided
Method: literature only
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV002054065.2
First in ClinVar: Jan 08, 2022 Last updated: Oct 01, 2022 |
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Comment:
Comment:
The MSH2 c.942+3A>T variant has been reported in the published literature in several affected individuals with Lynch Syndrome-related cancers (PMIDs: 23329266 (2013), 22949379 (2013), 24323032 (2014), 25117503 (2014), 28874130 (2017), 35734982 (2022), and 36421850 (2022)). A functional study demonstrated that this variant alters normal splicing and results in exon 5 skipping (PMID: 16395668 (2006)). It has also been described as the most common recurrent de novo germline variant in a human mismatch repair gene (PMID: 10978353 (2000)), as well as the most common Lynch Syndrome variant in the world (PMIDs: 20682701 (2010)). The frequency of this variant in the general population, 0.000033 (1/30582 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper MSH2 mRNA splicing. Based on the available information, this variant is classified as pathogenic.
Comment:
The MSH2 c.942+3A>T variant (rs193922376) is well-described in the literature to be associated with Lynch syndrome and colorectal cancer (Desai 2000, Lage 2004, Liu 1994, Woods 2010, Mismatch Repair Genes Variant Database and references therein). This variant is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 36580). This is an intronic variant in a moderately conserved nucleotide, and RNA analyses indicate this variant weakens the canonical donor splice site of intron 5 and leads to exon 5 skipping (Auclair 2006, Liu 1994). Based on available information, this variant is considered to be pathogenic. References: Link to Mismatch Repair Genes Variant Database: http://www.med.mun.ca/mmrvariants/search_results.aspx Auclair J et al. Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. Hum Mutat. 2006 Feb;27(2):145-54. PMID: 16395668. Desai DC et al. Recurrent germline mutation in MSH2 arises frequently de novo. J Med Genet. 2000 Sep;37(9):646-52. PMID: 10978353. Lage PA et al. Association of colonic and endometrial carcinomas in Portuguese families with hereditary nonpolyposis colorectal carcinoma significantly increases the probability of detecting a pathogenic mutation in mismatch repair genes, primarily the MSH2 gene. Cancer. 2004 Jul 1;101(1):172-7. PMID: 15222003. Liu B et al. hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res. 1994 Sep 1;54(17):4590-4. PMID: 8062247. Woods MO et al. The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease. Gut. 2010 Oct;59(10):1369-77. PMID: 20682701.
Comment:
The c.942+3A>T intronic pathogenic mutation results from an A to T substitution 3 nucleotides after coding exon 5 in the MSH2 gene. In one study, this mutation was found in eight unrelated Lynch syndrome families. Six of the eight families (75%) had one family member diagnosed with either a keratocanthoma or sebaceous adenoma associated with Muir-Torre syndrome, along with some combination of colon, uterine, and/or ureter transitional cell cancers in the family (South CD et al. J. Natl. Cancer Inst. 2008 Feb;100:277-81). This mutation was also reported in a German patient diagnosed with malignant fibrous histiocytoma (MFH) (Brieger A et al. Fam. Cancer. 2011 Sep;10:591-5). Authors of one study claim that this is the most common recurrent de novo germline mutation in a human mismatch repair gene, accounting for approximately 11% of all known pathogenic MSH2 gene mutations (Desai DC et al. J. Med. Genet. 2000 Sep;37:646-52). Multiple studies have demonstrated that this mutation results in an mRNA transcript lacking coding exon 5 (Casey G et al. JAMA. 2005 Feb;293:799-809; Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54; Arnold S et al. Hum. Mutat. 2009 May;30:757-70; Chong G et al. Hum. Mutat. 2009 Aug;30:E797-812). Of note, this mutation is also designated as IVS5+3A>T in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
Variant summary: MSH2 c.942+3A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5 prime splicing donor site; two predict the variant weakens a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Liu_1994). The variant allele was found at a frequency of 3.3e-05 in 30582 control chromosomes. c.942+3A>T has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Liu_1994, Thibodeau_1996, Chan_1999, Desai_2000, Green_2002, Win_2011). These data indicate that the variant is very likely to be associated with disease. Fourteen 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.
Comment:
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8062247].
Comment:
This variant causes an A to T nucleotide substitution at the +3 position of intron 5 of the MSH2 gene. RNA studies have shown this variant caused skipping of exon 5 (r.793_942del) and in-frame deletion of 50 amino acids in the DNA binding domain (PMID: 8062247, 16395668, 19267393). This variant has been reported as a recurrent de novo mutation in individuals affected with Lynch syndrome-associated cancer in different ethnicities (PMID: 10978353). This variant has been reported in many individuals and families with Lynch syndrome or suspected Lynch syndrome worldwide (PMID: 8062247, 10413423, 10446963, 11920650, 12112654, 12362047, 15222003, 16203774, 16395668, 17312306, 18625694, 19130300, 19419416, 20682701, 21681552, 22883484), and shown to segregate with Lynch syndrome cancers in family studies (PMID: 19267393). This variant is considered to be a founder mutation in the Newfoundland population (PMID: 20682701). This variant has been identified in 1/30582 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This variant causes an A to T nucleotide substitution at the +3 position of intron 5 of the MSH2 gene. RNA studies have shown this variant caused skipping of exon 5 (r.793_942del) and in-frame deletion of 50 amino acids in the DNA binding domain (PMID: 8062247, 16395668, 19267393). This variant has been reported as a recurrent de novo mutation in individuals affected with Lynch syndrome-associated cancer in different ethnicities (PMID: 10978353). This variant has been reported in many individuals and families with Lynch syndrome or suspected Lynch syndrome worldwide (PMID: 8062247, 10413423, 10446963, 11920650, 12112654, 12362047, 15222003, 16203774, 16395668, 17312306, 18625694, 19130300, 19419416, 20682701, 21681552, 22883484), and shown to segregate with Lynch syndrome cancers in family studies (PMID: 19267393). This variant is considered to be a founder mutation in the Newfoundland population (PMID: 20682701). This variant has been identified in 1/30582 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Originally reported to be a pathogenic founder variant in Newfoundland, but has since been hypothesized to be a mutational hotspot identified in individuals of varying ethnicities without a common haplotype identified (Desai 2000); Published functional studies demonstrate a damaging effect: skipping of exon 5 (Liu 1994, Auclair 2006); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Liu 1994, Froggatt 1999, Kurzawski 2005, Buchanan 2014, Rosty 2014, Harper 2016, Roth 2016, Ziada-Bouchaar 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 18270343, 10978353, 21598002, 8062247, 27064304, 26873718, 31857677, 25525159, 30702970, 29575718, 29665779, 30680046, 22883484, 25117503, 24323032, 23329266, 21642682, 23255516, 12362047, 19125127, 24603434, 19575290, 18809606, 25479140, 25345868, 10051005, 25648859, 25980754, 21056691, 22775459, 25110875, 20587412, 16395668, 22949379, 21636617, 27013479, 21681552, 26666765, 27468915, 26143115, 27601186, 27978560, 27357288, 27720647, 28243543, 19606495, 18566915, 28152038, 27713421, 28502729, 28514183, 26681312, 28873162, 28577310, 28874130, 29967423, 30093976, 31054147, 30553995, 25795746, 18460031, 31444830, 25025451, 32658311, 31615790, 33484353, 34178123, 31332305, 30875412, 30787465, 33726816)
Comment:
PP4, PP5, PM2, PS3, PS4_moderate
Comment:
This sequence change falls in intron 5 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 8062247, 10978353, 15222003, 19419416, 20682701, 21681552, 22883484, 24310308). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36580). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 5, but is expected to preserve the integrity of the reading-frame (PMID: 8062247, 16395668; Invitae). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.942+3A>T variant in MSH2 has been reported in >150 individuals with Lynch syndrome (LabCorp database, Woods 2010). This variant has been identified in 1/12862 of European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). In vitro functional studies show that the c.942+3A>T variant leads to an in-frame deletion of exon 5 (Auclair 2006). In addition, it has been classified as Pathogenic on December 18, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107794.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon the predicted impact to the protein, low frequency in controls and presence in affected individuals. ACMG/AMP Criteria applied: PS4, PM2, PS3_Supporting, PVS1_Strong.
Comment:
MSH2: PS3, PS4, PM2, PP1
Comment:
The MSH2 c.942+3A>T variant is predicted to interfere with splicing. This variant is a documented causative variant (germline and somatic) for several types of cancers (e.g. cancers of bladder, colorectal, ovarian, sebaceous gland, prostate etc.) (Haraldsdottir et al. 2014. PubMed ID: 25194673; Susswein et al. 2016, Table S1, PubMed ID: 26681312; Dominguez-Valentin et al. 2016, PubMed ID: 27013479). Also, it is a recurrent pathogenic variant of nonpolyposis colorectal cancer (Desai et al. 2000, PubMed ID: 10978353) and reported as both a de novo and a familial variant and represents above 10% of all MSH2 positive cases (Mangold et al. 2005, PubMed ID: 15849733). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/36580). This variant is interpreted as pathogenic.
Comment:
The MSH2 c.942+3A>T variant was identified in 12 of 2642 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer, and was not identified in 200 control chromosomes from healthy individuals (Auclair 2006, Brieger 2011, Canard 2012, Froggatt 1996, Grindedal 2009, Kurzawski 2002, Sheng 2008). The variant was also identified by our laboratory in 8 individuals with colorectal cancer. The variant was identified in dbSNP (ID: rs193922376) as “With Pathogenic allele”, Clinvitae database (as pathogenic), “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), ClinVar database (classified as pathogenic by InSight, Emory Genetics, Ambry genetics, Invitae, LabCorp, COGR, Mayo Clinic, GeneDx, OMIM) and UMD (111X with a “causal” classification). The c.942+3A>T variant is located at the donor splice site (or 3’ splice site of exon 5) but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. Furthermore, several population studies suggest the variant lead to an in-frame deletion of exon 5 and loss of MSH2 protein expression (Auclair 2006, Brieger 2011, Canard 2012, Kurzawski 2002). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
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sequence variant affecting splice donor
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University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)
Accession: SCV002318379.2
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Comment:
Multifactorial likelihood analysis posterior probability >0.99. Variant causes in-frame splicing aberration which interrupts know functional domains
Comment:
The MSH2 c.942+3A>T variant has been reported in the published literature in several affected individuals with Lynch Syndrome-related cancers (PMIDs: 23329266 (2013), 22949379 (2013), 24323032 (2014), 25117503 (2014), 28874130 (2017), 35734982 (2022), and 36421850 (2022)). A functional study demonstrated that this variant alters normal splicing and results in exon 5 skipping (PMID: 16395668 (2006)). It has also been described as the most common recurrent de novo germline variant in a human mismatch repair gene (PMID: 10978353 (2000)), as well as the most common Lynch Syndrome variant in the world (PMIDs: 20682701 (2010)). The frequency of this variant in the general population, 0.000033 (1/30582 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper MSH2 mRNA splicing. Based on the available information, this variant is classified as pathogenic.
Comment:
The MSH2 c.942+3A>T variant (rs193922376) is well-described in the literature to be associated with Lynch syndrome and colorectal cancer (Desai 2000, Lage 2004, Liu 1994, Woods 2010, Mismatch Repair Genes Variant Database and references therein). This variant is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 36580). This is an intronic variant in a moderately conserved nucleotide, and RNA analyses indicate this variant weakens the canonical donor splice site of intron 5 and leads to exon 5 skipping (Auclair 2006, Liu 1994). Based on available information, this variant is considered to be pathogenic. References: Link to Mismatch Repair Genes Variant Database: http://www.med.mun.ca/mmrvariants/search_results.aspx Auclair J et al. Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. Hum Mutat. 2006 Feb;27(2):145-54. PMID: 16395668. Desai DC et al. Recurrent germline mutation in MSH2 arises frequently de novo. J Med Genet. 2000 Sep;37(9):646-52. PMID: 10978353. Lage PA et al. Association of colonic and endometrial carcinomas in Portuguese families with hereditary nonpolyposis colorectal carcinoma significantly increases the probability of detecting a pathogenic mutation in mismatch repair genes, primarily the MSH2 gene. Cancer. 2004 Jul 1;101(1):172-7. PMID: 15222003. Liu B et al. hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res. 1994 Sep 1;54(17):4590-4. PMID: 8062247. Woods MO et al. The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease. Gut. 2010 Oct;59(10):1369-77. PMID: 20682701.
Comment:
The c.942+3A>T intronic pathogenic mutation results from an A to T substitution 3 nucleotides after coding exon 5 in the MSH2 gene. In one study, this mutation was found in eight unrelated Lynch syndrome families. Six of the eight families (75%) had one family member diagnosed with either a keratocanthoma or sebaceous adenoma associated with Muir-Torre syndrome, along with some combination of colon, uterine, and/or ureter transitional cell cancers in the family (South CD et al. J. Natl. Cancer Inst. 2008 Feb;100:277-81). This mutation was also reported in a German patient diagnosed with malignant fibrous histiocytoma (MFH) (Brieger A et al. Fam. Cancer. 2011 Sep;10:591-5). Authors of one study claim that this is the most common recurrent de novo germline mutation in a human mismatch repair gene, accounting for approximately 11% of all known pathogenic MSH2 gene mutations (Desai DC et al. J. Med. Genet. 2000 Sep;37:646-52). Multiple studies have demonstrated that this mutation results in an mRNA transcript lacking coding exon 5 (Casey G et al. JAMA. 2005 Feb;293:799-809; Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54; Arnold S et al. Hum. Mutat. 2009 May;30:757-70; Chong G et al. Hum. Mutat. 2009 Aug;30:E797-812). Of note, this mutation is also designated as IVS5+3A>T in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
Variant summary: MSH2 c.942+3A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5 prime splicing donor site; two predict the variant weakens a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Liu_1994). The variant allele was found at a frequency of 3.3e-05 in 30582 control chromosomes. c.942+3A>T has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Liu_1994, Thibodeau_1996, Chan_1999, Desai_2000, Green_2002, Win_2011). These data indicate that the variant is very likely to be associated with disease. Fourteen 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.
Comment:
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8062247].
Comment:
This variant causes an A to T nucleotide substitution at the +3 position of intron 5 of the MSH2 gene. RNA studies have shown this variant caused skipping of exon 5 (r.793_942del) and in-frame deletion of 50 amino acids in the DNA binding domain (PMID: 8062247, 16395668, 19267393). This variant has been reported as a recurrent de novo mutation in individuals affected with Lynch syndrome-associated cancer in different ethnicities (PMID: 10978353). This variant has been reported in many individuals and families with Lynch syndrome or suspected Lynch syndrome worldwide (PMID: 8062247, 10413423, 10446963, 11920650, 12112654, 12362047, 15222003, 16203774, 16395668, 17312306, 18625694, 19130300, 19419416, 20682701, 21681552, 22883484), and shown to segregate with Lynch syndrome cancers in family studies (PMID: 19267393). This variant is considered to be a founder mutation in the Newfoundland population (PMID: 20682701). This variant has been identified in 1/30582 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This variant causes an A to T nucleotide substitution at the +3 position of intron 5 of the MSH2 gene. RNA studies have shown this variant caused skipping of exon 5 (r.793_942del) and in-frame deletion of 50 amino acids in the DNA binding domain (PMID: 8062247, 16395668, 19267393). This variant has been reported as a recurrent de novo mutation in individuals affected with Lynch syndrome-associated cancer in different ethnicities (PMID: 10978353). This variant has been reported in many individuals and families with Lynch syndrome or suspected Lynch syndrome worldwide (PMID: 8062247, 10413423, 10446963, 11920650, 12112654, 12362047, 15222003, 16203774, 16395668, 17312306, 18625694, 19130300, 19419416, 20682701, 21681552, 22883484), and shown to segregate with Lynch syndrome cancers in family studies (PMID: 19267393). This variant is considered to be a founder mutation in the Newfoundland population (PMID: 20682701). This variant has been identified in 1/30582 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Originally reported to be a pathogenic founder variant in Newfoundland, but has since been hypothesized to be a mutational hotspot identified in individuals of varying ethnicities without a common haplotype identified (Desai 2000); Published functional studies demonstrate a damaging effect: skipping of exon 5 (Liu 1994, Auclair 2006); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Liu 1994, Froggatt 1999, Kurzawski 2005, Buchanan 2014, Rosty 2014, Harper 2016, Roth 2016, Ziada-Bouchaar 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 18270343, 10978353, 21598002, 8062247, 27064304, 26873718, 31857677, 25525159, 30702970, 29575718, 29665779, 30680046, 22883484, 25117503, 24323032, 23329266, 21642682, 23255516, 12362047, 19125127, 24603434, 19575290, 18809606, 25479140, 25345868, 10051005, 25648859, 25980754, 21056691, 22775459, 25110875, 20587412, 16395668, 22949379, 21636617, 27013479, 21681552, 26666765, 27468915, 26143115, 27601186, 27978560, 27357288, 27720647, 28243543, 19606495, 18566915, 28152038, 27713421, 28502729, 28514183, 26681312, 28873162, 28577310, 28874130, 29967423, 30093976, 31054147, 30553995, 25795746, 18460031, 31444830, 25025451, 32658311, 31615790, 33484353, 34178123, 31332305, 30875412, 30787465, 33726816)
Comment:
PP4, PP5, PM2, PS3, PS4_moderate
Comment:
This sequence change falls in intron 5 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 8062247, 10978353, 15222003, 19419416, 20682701, 21681552, 22883484, 24310308). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36580). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 5, but is expected to preserve the integrity of the reading-frame (PMID: 8062247, 16395668; Invitae). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.942+3A>T variant in MSH2 has been reported in >150 individuals with Lynch syndrome (LabCorp database, Woods 2010). This variant has been identified in 1/12862 of European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). In vitro functional studies show that the c.942+3A>T variant leads to an in-frame deletion of exon 5 (Auclair 2006). In addition, it has been classified as Pathogenic on December 18, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107794.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon the predicted impact to the protein, low frequency in controls and presence in affected individuals. ACMG/AMP Criteria applied: PS4, PM2, PS3_Supporting, PVS1_Strong.
Comment:
MSH2: PS3, PS4, PM2, PP1
Comment:
The MSH2 c.942+3A>T variant is predicted to interfere with splicing. This variant is a documented causative variant (germline and somatic) for several types of cancers (e.g. cancers of bladder, colorectal, ovarian, sebaceous gland, prostate etc.) (Haraldsdottir et al. 2014. PubMed ID: 25194673; Susswein et al. 2016, Table S1, PubMed ID: 26681312; Dominguez-Valentin et al. 2016, PubMed ID: 27013479). Also, it is a recurrent pathogenic variant of nonpolyposis colorectal cancer (Desai et al. 2000, PubMed ID: 10978353) and reported as both a de novo and a familial variant and represents above 10% of all MSH2 positive cases (Mangold et al. 2005, PubMed ID: 15849733). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/36580). This variant is interpreted as pathogenic.
Comment:
The MSH2 c.942+3A>T variant was identified in 12 of 2642 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer, and was not identified in 200 control chromosomes from healthy individuals (Auclair 2006, Brieger 2011, Canard 2012, Froggatt 1996, Grindedal 2009, Kurzawski 2002, Sheng 2008). The variant was also identified by our laboratory in 8 individuals with colorectal cancer. The variant was identified in dbSNP (ID: rs193922376) as “With Pathogenic allele”, Clinvitae database (as pathogenic), “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), ClinVar database (classified as pathogenic by InSight, Emory Genetics, Ambry genetics, Invitae, LabCorp, COGR, Mayo Clinic, GeneDx, OMIM) and UMD (111X with a “causal” classification). The c.942+3A>T variant is located at the donor splice site (or 3’ splice site of exon 5) but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. Furthermore, several population studies suggest the variant lead to an in-frame deletion of exon 5 and loss of MSH2 protein expression (Auclair 2006, Brieger 2011, Canard 2012, Kurzawski 2002). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Prevalence and Genotype-Phenotype Correlation of Lynch Syndrome in a Selected High-Risk Cohort from Qatar's Population. | Sidenna M | Genes | 2022 | PMID: 36421850 |
| Germline variants screening of MLH1, MSH2, MSH6 and PMS2 genes in 64 Algerian Lynch syndrome families: The first nationwide study. | Boumehdi AL | Annals of human genetics | 2022 | PMID: 36073783 |
| Multigene Panel Testing in Turkish Hereditary Cancer Syndrome Patients. | Arslan Ates E | Medeniyet medical journal | 2022 | PMID: 35734982 |
| Development and external validation of a novel nomogram for screening Chinese Lynch syndrome: based on a multicenter, population study. | Yang M | Therapeutic advances in medical oncology | 2021 | PMID: 34178123 |
| Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients. | Stranneheim H | Genome medicine | 2021 | PMID: 33726816 |
| Prevalence of mutations in BRCA and MMR genes in patients affected with hereditary endometrial cancer. | Vietri MT | Medical oncology (Northwood, London, England) | 2021 | PMID: 33484353 |
| Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls. | Akcay IM | International journal of cancer | 2021 | PMID: 32658311 |
| Lynch Syndrome. | Adam MP | - | 2021 | PMID: 20301390 |
| Retained mismatch repair protein expression occurs in approximately 6% of microsatellite instability-high cancers and is associated with missense mutations in mismatch repair genes. | Hechtman JF | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2020 | PMID: 31857677 |
| Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome. | Wischhusen JW | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2020 | PMID: 31615790 |
| Fumarate hydratase FH c.1431_1433dupAAA (p.Lys477dup) variant is not associated with cancer including renal cell carcinoma. | Zhang L | Human mutation | 2020 | PMID: 31444830 |
| Full-length transcript amplification and sequencing as universal method to test mRNA integrity and biallelic expression in mismatch repair genes. | Morak M | European journal of human genetics : EJHG | 2019 | PMID: 31332305 |
| Screening for hereditary cancers in patients with endometrial cancer reveals a high frequency of germline mutations in cancer predisposition genes. | Tian W | International journal of cancer | 2019 | PMID: 31054147 |
| Discoveries beyond BRCA1/2: Multigene testing in an Asian multi-ethnic cohort suspected of hereditary breast cancer syndrome in the real world. | Ow SGW | PloS one | 2019 | PMID: 30875412 |
| Toward automation of germline variant curation in clinical cancer genetics. | Ravichandran V | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30787465 |
| Comprehensive Paired Tumor/Germline Testing for Lynch Syndrome: Bringing Resolution to the Diagnostic Process. | Salvador MU | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2019 | PMID: 30702970 |
| DNA variants in Helicobacter pylori infected patients with chronic gastritis, dysplasia and gastric cancer. | Hnatyszyn A | Advances in medical sciences | 2019 | PMID: 30553995 |
| Modified capture-recapture estimates of the number of families with Lynch syndrome in Central Ohio. | Ranola JMO | Familial cancer | 2019 | PMID: 30019097 |
| Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers. | Chan GHJ | Oncotarget | 2018 | PMID: 30093976 |
| Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome. | Schneider NB | Cancer medicine | 2018 | PMID: 29575718 |
| Screening for germline mutations in mismatch repair genes in patients with Lynch syndrome by next generation sequencing. | Soares BL | Familial cancer | 2018 | PMID: 28932927 |
| A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. | Rossi BM | BMC cancer | 2017 | PMID: 28874130 |
| Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population. | Lagerstedt-Robinson K | Oncology reports | 2016 | PMID: 27601186 |
| Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
| Diagnostic error: what Muir-Torre syndrome has taught us. | Wall D | BMJ case reports | 2015 | PMID: 25795746 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. | Rosty C | Familial cancer | 2014 | PMID: 25117503 |
| The histomorphology of Lynch syndrome-associated ovarian carcinomas: toward a subtype-specific screening strategy. | Chui MH | The American journal of surgical pathology | 2014 | PMID: 25025451 |
| Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing. | Buchanan DD | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2014 | PMID: 24323032 |
| ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). | Hegde M | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24310308 |
| Splice site mutations in mismatch repair genes and risk of cancer in the general population. | Thomsen M | Familial cancer | 2013 | PMID: 23329266 |
| A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry. | Thompson BA | Human mutation | 2013 | PMID: 22949379 |
| Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. | Skeldon SC | European urology | 2013 | PMID: 22883484 |
| Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals. | Valentin MD | Familial cancer | 2011 | PMID: 21681552 |
| Determining the frequency of de novo germline mutations in DNA mismatch repair genes. | Win AK | Journal of medical genetics | 2011 | PMID: 21636617 |
| Malignant fibrous histiocytoma is a rare Lynch syndrome-associated tumor in two German families. | Brieger A | Familial cancer | 2011 | PMID: 21598002 |
| The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease. | Woods MO | Gut | 2010 | PMID: 20682701 |
| A study on MSH2 and MLH1 mutations in hereditary nonpolyposis colorectal cancer families from the Basque Country, describing four new germline mutations. | Martínez-Bouzas C | Familial cancer | 2009 | PMID: 19760518 |
| High frequency of exon deletions and putative founder effects in French Canadian Lynch syndrome families. | Chong G | Human mutation | 2009 | PMID: 19459153 |
| 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 |
| Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics. | Arnold S | Human mutation | 2009 | PMID: 19267393 |
| Sarcomas associated with hereditary nonpolyposis colorectal cancer: broad anatomical and morphological spectrum. | Nilbert M | Familial cancer | 2009 | PMID: 19130300 |
| Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. | Nilbert M | Familial cancer | 2009 | PMID: 18566915 |
| A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting. | Ramsoekh D | Gut | 2008 | PMID: 18625694 |
| Malignant melanoma in patients with hereditary nonpolyposis colorectal cancer. | Ponti G | The British journal of dermatology | 2008 | PMID: 18460031 |
| The frequency of Muir-Torre syndrome among Lynch syndrome families. | South CD | Journal of the National Cancer Institute | 2008 | PMID: 18270343 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. | Lagerstedt Robinson K | Journal of the National Cancer Institute | 2007 | PMID: 17312306 |
| Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. | Auclair J | Human mutation | 2006 | PMID: 16395668 |
| High frequency of hereditary colorectal cancer in Newfoundland likely involves novel susceptibility genes. | Woods MO | Clinical cancer research : an official journal of the American Association for Cancer Research | 2005 | PMID: 16203774 |
| Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. | Casey G | JAMA | 2005 | PMID: 15713769 |
| Association of colonic and endometrial carcinomas in Portuguese families with hereditary nonpolyposis colorectal carcinoma significantly increases the probability of detecting a pathogenic mutation in mismatch repair genes, primarily the MSH2 gene. | Lage PA | Cancer | 2004 | PMID: 15222003 |
| Germline MSH2 and MLH1 mutational spectrum in HNPCC families from Poland and the Baltic States. | Kurzawski G | Journal of medical genetics | 2002 | PMID: 12362047 |
| Impact of gender and parent of origin on the phenotypic expression of hereditary nonpolyposis colorectal cancer in a large Newfoundland kindred with a common MSH2 mutation. | Green J | Diseases of the colon and rectum | 2002 | PMID: 12352241 |
| Hereditary non-polyposis colorectal cancer (HNPCC): phenotype-genotype correlation between patients with and without identified mutation. | Bisgaard ML | Human mutation | 2002 | PMID: 12112654 |
| Prevalence of germline mutations of MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer families from Spain. | Caldes T | International journal of cancer | 2002 | PMID: 11920650 |
| Recurrent germline mutation in MSH2 arises frequently de novo. | Desai DC | Journal of medical genetics | 2000 | PMID: 10978353 |
| Unbalanced germ-line expression of hMLH1 and hMSH2 alleles in hereditary nonpolyposis colorectal cancer. | Curia MC | Cancer research | 1999 | PMID: 10446963 |
| Frequent microsatellite instability and mismatch repair gene mutations in young Chinese patients with colorectal cancer. | Chan TL | Journal of the National Cancer Institute | 1999 | PMID: 10413423 |
| A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer. | Froggatt NJ | Journal of medical genetics | 1999 | PMID: 10051005 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. | Thibodeau SN | Cancer research | 1996 | PMID: 8895729 |
| 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 |
| hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. | Liu B | Cancer research | 1994 | PMID: 8062247 |
| Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. | Leach FS | Cell | 1993 | PMID: 8261515 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MSH2 | - | - | - | - |
| http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.942%2B3A%3ET | - | - | - | - |
| - | - | - | - | DOI: 10.1158/1538-7445.AM2019-655 |
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Text-mined citations for rs193922376 ...
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Record last updated Oct 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.