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MSH2 (human mutS homolog 2)

Written2005-07Enric Domingo, Sim Schwartz Jr
Oncologia Molecular i Envelliment, Centre d'Investigacions en Bioqumica i Biologia Molecular (CIBBIM) Hospital Universitari Vall d'Hebron Passeig Vall d'Hebron 119-129 Barcelona 08035, Catalonia, Spain

(Note : for Links provided by Atlas : click)

Identity

Other namesCOCA1
FCC1
hMSH2
HNPCC1
HGNC (Hugo) MSH2
LocusID (NCBI) 4436
Atlas_Id 340
Location 2p21  [Link to chromosome band 2p21]
Location_base_pair Starts at 47630206 and ends at 47710367 bp from pter ( according to hg19-Feb_2009)  [Mapping MSH2.png]
Local_order Between the FLJ40172 and MSH6 genes.
Fusion genes
(updated 2016)
CCDC149 (4p15.2) / MSH2 (2p21)DNAI1 (9p13.3) / MSH2 (2p21)EPCAM (2p21) / MSH2 (2p21)
MSH2 (2p21) / AC018682.6 ()MSH2 (2p21) / MSH2 (2p21)MSH2 (2p21) / SLC3A1 (2p21)
MSH2 (2p21) / TTC7A (2p21)PARP12 (7q34) / MSH2 (2p21)REEP3 (10q21.3) / MSH2 (2p21)

DNA/RNA

 
  Diagram of the MSH2 gene. Exons are represented by boxes (in scale) transcribed and untranscribed sequences in blue and yellow, with exon numbers on top and number of base pairs at the bottom. Introns are represented by black bars (not in scale) and the number of base pairs indicated. The arrows show the ATG and the stop codons respectively.
Description The MSH2 gene is composed of 16 exons spanning in a region of 80098 bp.
Transcription The transcribed mRNA has 3145 bp.

Protein

 
  Diagram of the MSH2 protein in scale. Numbers inside the blue boxes indicate the exon from which is translated each part of the protein. The boxes inside represent the DNA binding domain (red), the hMSH3/hMSH6 interaction domain (yellow) and the MutL homologs interaction domain (green); C: Carboxyl-terminal; N: Amino-terminal.
Description Aminoacids: 934. Molecular Weight: 104.7 kDa. MSH2 is a protein involved in the mismatch repair process after DNA replication. It contains a DNA binding domain and two interaction domains, one for MSH3 or MSH6 and the other for MutL homologs (MLH1 and PMS2), located in two different regions of the gene.
Localisation Nuclear
Function MSH2 can bind to MSH6 or to MSH3 to form the MutS alpha or the MutS beta complexes respectively. While MutS alpha complex binds to base-base and insertion-deletion mismatches, MutS beta only binds to insertion-deletion mismatches. Upon binding to the mismatch, the MutS complex associates with the MutL complex (composed of MLH1 and PMS2), and recruits the proteins needed for DNA excision and repair. (See also: Repair of DNA double-strand breaks
Homology MSH2 is homologue to the bacterial MutS gene and MSH2 homologues are also present in eukaryotes.

Mutations

Germinal There are over 300 MSH2 germline mutations described along the gene that cause hereditary non-polyposis colorectal cancer (HNPCC, see below). Mutations do not occur in any particular hotspot or region of the gene and include either nucleotide substitutions (missense, nonsense and splicing errors) and insertions/deletions (gross or small). In most of these mutations the resulting protein is truncated. Although rare there are described some founding mutations which account for a high proportion of the HNPCC tumours in some specific populations. Some germline genetic changes have also been described in exons and introns as non pathogenic.
Somatic Some sporadic mismatch repair deficient cases (sporadic MSI) with somatic MSH2 mutations are described.

Implicated in

Note
Entity HNPCC (Hereditary Non Polyposis Colorectal Cancer)
Disease Predisposition to develop cancer, preferentially colorectal, but also in endometrium, , urinary tract, stomach, small bowel, biliary tract and brain.
Oncogenesis MSH2 mutations in HNPCC account for about 25% of the total cases approximately. These mutations are inherited in one allele and later the other allele is lost by LOH. This leads to mismatch repair deficiency in this patients, which is the cause of the accumulation of mutations along the genome, causing microsatellite instability (MSI) and promoting tumorigenesis. It has also been described that low levels of MSI characterize MLH1 and MSH2 HNPCC carriers before tumour diagnosis.
  
Entity MSI (MicroSatellite Instability)
Note Tumours in which the molecular feature that leads to cancer is the lost of the mismatch repair (MMR) system.
Disease This phenotype is present in 15% of colorectal, gastric and endometrial cancer, and has a lower incidence in some other tissues.
Prognosis MSI tumours have better prognosis than the MicroSatellite Stable (MSS).
Oncogenesis Few sporadic cases and about 25% of the HNPCC are due to different mutations in MSH2. These mutations are germline in HNPCC.
  
Entity Muir-Torre syndrome
Disease Coincidence of at least one sebaceous adenoma, epithelioma or carcinoma and one internal malignancy.
Oncogenesis Muir-Torre syndrome is mainly due to inherited MSH2 mutations.
  

Bibliography

Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis.
Alazzouzi H, Domingo E, Gonz´lez S, Blanco I, Armengol M, Espín E, Plaja A, Schwartz S, Capella G, Schwartz S Jr
Human molecular genetics. 2005 ; 14 (2) : 235-239.
PMID 15563510
 
Microsatellite instability in inherited and sporadic neoplasms.
Eshleman JR, Markowitz SD
Current opinion in oncology. 1995 ; 7 (1) : 83-89.
PMID 7696368
 
The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.
Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R
Cell. 1993 ; 75 (5) : 1027-1038.
PMID 8252616
 
DNA mismatch repair defects: role in colorectal carcinogenesis.
Jacob S, Praz F
Biochimie. 2002 ; 84 (1) : 27-47.
PMID 11900875
 
A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States.
Lynch HT, Coronel SM, Okimoto R, Hampel H, Sweet K, Lynch JF, Barrows A, Wijnen J, van der Klift H, Franken P, Wagner A, Fodde R, de la Chapelle A
JAMA : the journal of the American Medical Association. 2004 ; 291 (6) : 718-724.
PMID 14871915
 
A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome.
Mangold E, Pagenstecher C, Leister M, Mathiak M, Rütten A, Friedl W, Propping P, Ruzicka T, Kruse R
Journal of medical genetics. 2004 ; 41 (7) : 567-572.
PMID 15235030
 
DNA mismatch repair and mutation avoidance pathways.
Marti TM, Kunz C, Fleck O
Journal of cellular physiology. 2002 ; 191 (1) : 28-41.
PMID 11920679
 
Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review.
Mitchell RJ, Farrington SM, Dunlop MG, Campbell H
American journal of epidemiology. 2002 ; 156 (10) : 885-902.
PMID 12419761
 

Citation

This paper should be referenced as such :
Domingo, E ; Schwartz, S Jr
MSH2 (human mutS homolog 2)
Atlas Genet Cytogenet Oncol Haematol. 2005;9(4):291-292.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MSH2ID340ch2p22.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 6 ]
  Breast tumors : an overview
Colon: Colorectal adenocarcinoma
Breast: Ductal carcinoma
Gastric Tumors: an overview
Liver tumors: an overview
Head and Neck: Oral leukoplakia
Uterus Tumours: an Overview

Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 4 ]
  Familial nervous system tumour syndromes Hereditary pancreatic cancer Hereditary non polyposis colorectal carcinoma (HNPCC Syndrome) Turcot syndrome

External links

Nomenclature
HGNC (Hugo)MSH2   7325
Cards
AtlasMSH2ID340ch2p22
Entrez_Gene (NCBI)MSH2  4436  mutS homolog 2
AliasesCOCA1; FCC1; HNPCC; HNPCC1; 
LCFS2
GeneCards (Weizmann)MSH2
Ensembl hg19 (Hinxton)ENSG00000095002 [Gene_View]  chr2:47630206-47710367 [Contig_View]  MSH2 [Vega]
Ensembl hg38 (Hinxton)ENSG00000095002 [Gene_View]  chr2:47630206-47710367 [Contig_View]  MSH2 [Vega]
ICGC DataPortalENSG00000095002
TCGA cBioPortalMSH2
AceView (NCBI)MSH2
Genatlas (Paris)MSH2
WikiGenes4436
SOURCE (Princeton)MSH2
Genomic and cartography
GoldenPath hg19 (UCSC)MSH2  -     chr2:47630206-47710367 +  2p21   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)MSH2  -     2p21   [Description]    (hg38-Dec_2013)
EnsemblMSH2 - 2p21 [CytoView hg19]  MSH2 - 2p21 [CytoView hg38]
Mapping of homologs : NCBIMSH2 [Mapview hg19]  MSH2 [Mapview hg38]
OMIM120435   158320   276300   609309   
Gene and transcription
Genbank (Entrez)AK222860 AK223284 AK296831 AK297763 AK299667
RefSeq transcript (Entrez)NM_000251 NM_001258281
RefSeq genomic (Entrez)NC_000002 NC_018913 NG_007110 NT_022184 NW_004929300
Consensus coding sequences : CCDS (NCBI)MSH2
Cluster EST : UnigeneHs.597656 [ NCBI ]
CGAP (NCI)Hs.597656
Alternative Splicing GalleryENSG00000095002
Gene ExpressionMSH2 [ NCBI-GEO ]   MSH2 [ EBI - ARRAY_EXPRESS ]   MSH2 [ SEEK ]   MSH2 [ MEM ]
Gene Expression Viewer (FireBrowse)MSH2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4436
GTEX Portal (Tissue expression)MSH2
Protein : pattern, domain, 3D structure
UniProt/SwissProtP43246 (Uniprot)
NextProtP43246  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP43246
Splice isoforms : SwissVarP43246 (Swissvar)
PhosPhoSitePlusP43246
Domaine pattern : Prosite (Expaxy)DNA_MISMATCH_REPAIR_2 (PS00486)   
Domains : Interpro (EBI)DNA_mismatch_repair_MutS    DNA_mismatch_repair_MutS-lik_N    DNA_mismatch_repair_MutS_C    DNA_mismatch_repair_MutS_clamp    DNA_mismatch_repair_MutS_core    DNA_mmatch_repair_MutS_con_dom    Msh2    P-loop_NTPase   
Domain families : Pfam (Sanger)MutS_I (PF01624)    MutS_II (PF05188)    MutS_III (PF05192)    MutS_IV (PF05190)    MutS_V (PF00488)   
Domain families : Pfam (NCBI)pfam01624    pfam05188    pfam05192    pfam05190    pfam00488   
Domain families : Smart (EMBL)MUTSac (SM00534)  MUTSd (SM00533)  
DMDM Disease mutations4436
Blocks (Seattle)MSH2
PDB (SRS)2O8B    2O8C    2O8D    2O8E    2O8F    3THW    3THX    3THY    3THZ   
PDB (PDBSum)2O8B    2O8C    2O8D    2O8E    2O8F    3THW    3THX    3THY    3THZ   
PDB (IMB)2O8B    2O8C    2O8D    2O8E    2O8F    3THW    3THX    3THY    3THZ   
PDB (RSDB)2O8B    2O8C    2O8D    2O8E    2O8F    3THW    3THX    3THY    3THZ   
Structural Biology KnowledgeBase2O8B    2O8C    2O8D    2O8E    2O8F    3THW    3THX    3THY    3THZ   
SCOP (Structural Classification of Proteins)2O8B    2O8C    2O8D    2O8E    2O8F    3THW    3THX    3THY    3THZ   
CATH (Classification of proteins structures)2O8B    2O8C    2O8D    2O8E    2O8F    3THW    3THX    3THY    3THZ   
SuperfamilyP43246
Human Protein AtlasENSG00000095002
Peptide AtlasP43246
HPRD00389
IPIIPI00017303   IPI01012696   IPI00942143   IPI01014700   IPI00940255   IPI00940797   IPI00816513   IPI00783348   IPI00783458   IPI00942418   IPI00893933   
Protein Interaction databases
DIP (DOE-UCLA)P43246
IntAct (EBI)P43246
FunCoupENSG00000095002
BioGRIDMSH2
STRING (EMBL)MSH2
ZODIACMSH2
Ontologies - Pathways
QuickGOP43246
Ontology : AmiGOmagnesium ion binding  four-way junction DNA binding  Y-form DNA binding  heteroduplex DNA loop binding  double-strand/single-strand DNA junction binding  meiotic mismatch repair  nuclear chromosome, telomeric region  in utero embryonic development  DNA binding  double-stranded DNA binding  single-stranded DNA binding  protein binding  protein binding  ATP binding  nucleoplasm  oxidative phosphorylation  DNA repair  mismatch repair  mismatch repair  mismatch repair  postreplication repair  double-strand break repair  meiotic gene conversion  cell cycle arrest  reciprocal meiotic recombination  germ cell development  protein C-terminus binding  determination of adult lifespan  male gonad development  response to X-ray  response to X-ray  response to UV-B  response to UV-B  membrane  somatic hypermutation of immunoglobulin genes  somatic recombination of immunoglobulin gene segments  ATPase activity  centromeric DNA binding  B cell mediated immunity  enzyme binding  protein kinase binding  B cell differentiation  mismatched DNA binding  intra-S DNA damage checkpoint  guanine/thymine mispair binding  guanine/thymine mispair binding  dinucleotide insertion or deletion binding  single guanine insertion binding  single thymine insertion binding  dinucleotide repeat insertion binding  MutSalpha complex  MutSbeta complex  oxidized purine DNA binding  MutLalpha complex binding  intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  protein homodimerization activity  negative regulation of neuron apoptotic process  ADP binding  maintenance of DNA repeat elements  negative regulation of reciprocal meiotic recombination  isotype switching  isotype switching  negative regulation of DNA recombination  negative regulation of DNA recombination  positive regulation of helicase activity  
Ontology : EGO-EBImagnesium ion binding  four-way junction DNA binding  Y-form DNA binding  heteroduplex DNA loop binding  double-strand/single-strand DNA junction binding  meiotic mismatch repair  nuclear chromosome, telomeric region  in utero embryonic development  DNA binding  double-stranded DNA binding  single-stranded DNA binding  protein binding  protein binding  ATP binding  nucleoplasm  oxidative phosphorylation  DNA repair  mismatch repair  mismatch repair  mismatch repair  postreplication repair  double-strand break repair  meiotic gene conversion  cell cycle arrest  reciprocal meiotic recombination  germ cell development  protein C-terminus binding  determination of adult lifespan  male gonad development  response to X-ray  response to X-ray  response to UV-B  response to UV-B  membrane  somatic hypermutation of immunoglobulin genes  somatic recombination of immunoglobulin gene segments  ATPase activity  centromeric DNA binding  B cell mediated immunity  enzyme binding  protein kinase binding  B cell differentiation  mismatched DNA binding  intra-S DNA damage checkpoint  guanine/thymine mispair binding  guanine/thymine mispair binding  dinucleotide insertion or deletion binding  single guanine insertion binding  single thymine insertion binding  dinucleotide repeat insertion binding  MutSalpha complex  MutSbeta complex  oxidized purine DNA binding  MutLalpha complex binding  intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  protein homodimerization activity  negative regulation of neuron apoptotic process  ADP binding  maintenance of DNA repeat elements  negative regulation of reciprocal meiotic recombination  isotype switching  isotype switching  negative regulation of DNA recombination  negative regulation of DNA recombination  positive regulation of helicase activity  
Pathways : KEGGMismatch repair    Pathways in cancer    Colorectal cancer   
REACTOMEP43246 [protein]
REACTOME PathwaysR-HSA-5358606 Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta) [pathway]
REACTOME PathwaysR-HSA-5358565 Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) [pathway]
NDEx NetworkMSH2
Atlas of Cancer Signalling NetworkMSH2
Wikipedia pathwaysMSH2
Orthology - Evolution
OrthoDB4436
GeneTree (enSembl)ENSG00000095002
Phylogenetic Trees/Animal Genes : TreeFamMSH2
Homologs : HomoloGeneMSH2
Homology/Alignments : Family Browser (UCSC)MSH2
Gene fusions - Rearrangements
Fusion: TCGAMSH2 2p21 AC018682.6 BRCA
Fusion: TCGAMSH2 2p21 SLC3A1 2p21 BRCA
Fusion: TCGAMSH2 2p21 TTC7A 2p21 BRCA
Polymorphisms : SNP, variants
NCBI Variation ViewerMSH2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MSH2
dbVarMSH2
ClinVarMSH2
1000_GenomesMSH2 
Exome Variant ServerMSH2
ExAC (Exome Aggregation Consortium)MSH2 (select the gene name)
Genetic variants : HAPMAP4436
Genomic Variants (DGV)MSH2 [DGVbeta]
Mutations
ICGC Data PortalMSH2 
TCGA Data PortalMSH2 
Broad Tumor PortalMSH2
OASIS PortalMSH2 [ Somatic mutations - Copy number]
Cancer Gene: CensusMSH2 
Somatic Mutations in Cancer : COSMICMSH2 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)Colon cancer gene variant databases
LOVD (Leiden Open Variation Database)LOVD - human mismatch repair genes
LOVD (Leiden Open Variation Database)Zhejiang University Center for Genetic and Genomic Medicine (ZJU-CGGM)
BioMutasearch MSH2
DgiDB (Drug Gene Interaction Database)MSH2
DoCM (Curated mutations)MSH2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MSH2 (select a term)
intoGenMSH2
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)2:47630206-47710367  ENSG00000095002
CONAN: Copy Number AnalysisMSH2 
Mutations and Diseases : HGMDMSH2
OMIM120435    158320    276300    609309   
MedgenMSH2
Genetic Testing Registry MSH2
NextProtP43246 [Medical]
TSGene4436
GENETestsMSH2
Huge Navigator MSH2 [HugePedia]
snp3D : Map Gene to Disease4436
BioCentury BCIQMSH2
ClinGenMSH2 (curated)
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4436
Chemical/Pharm GKB GenePA31133
Drug Sensitivity MSH2
Clinical trialMSH2
Miscellaneous
canSAR (ICR)MSH2 (select the gene name)
Other databaseUMD-MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli)). Curator: S. Olschwang
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMSH2
EVEXMSH2
GoPubMedMSH2
iHOPMSH2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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