Atlas of Genetics and Cytogenetics in Oncology and Haematology

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MLH1 (human mutL homolog 1)

Written2005-02Enrico Domingo, Simo 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)


Other aliasCOCA2
LocusID (NCBI) 4292
Atlas_Id 149
Location 3p22.2  [Link to chromosome band 3p22]
Location_base_pair Starts at and ends at bp from pter
Local_order Between the KIAA0342 and LRRFIP2 genes
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
GOLGA4 (3p22.2) / MLH1 (3p22.2)HMGA1 (6p21.31) / MLH1 (3p22.2)IRS2 (13q34) / MLH1 (3p22.2)
LRRFIP2 (3p22.2) / MLH1 (3p22.2)MALAT1 (11q13.1) / MLH1 (3p22.2)MLH1 (3p22.2) / ITGA9 (3p22.2)
MLH1 (3p22.2) / MLH1 (3p22.2)UBAP2 (9p13.3) / MLH1 (3p22.2)


  Diagram of the MLH1 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 MLH1 gene is composed of 19 exons spanning in a region of 57360 bp.
Transcription The transcribed mRNA has 2524 bp


  Diagram of the MLH1 protein in scale. Numbers inside the blue boxes indicate the exon from which is translated each part of the protein. The three boxes inside represent the ATPase domain, the MutS homologs interaction domain and the PMS2/MLH3/PMS1 interaction domain; C: Carboxyl-terminal; N: Amino-terminal
Description Aminoacids: 756. Molecular Weight: 84.6 kDa. MLH1 is a protein involved in the mismatch repair process after DNA replication. It contains an ATPase domain and two interaction domains, one for MutS homologs (MSH2, MSH3, MSH6) and the other for PMS2, MLH3 or PMS1.
Localisation Nuclear
Function MLH1 has no known enzymatic activity. MLH1 forms a heterodimer with PMS2 known as MutLa, although it can also bind to PMS1 or MLH3. This heterodimeric complex binds to the heteroduplexes MutSa (composed of MSH2 and MSH6) or MutSb (composed of MSH2 and MSH3), which recognize DNA lesions. The heterodimer formed by MLH1 is responsible for the recruitment of the proteins needed for the excision and repair synthesis.
Homology MLH1 is homologue to the bacterial MutL gene, specially in the N-terminal region, and MLH1 homologues are also present in eukaryotes (for example in Mus musculus, Drosophila melanogaster, Caenorhabditis elegans or Saccharomyces cerevisae)


Germinal There are over 300 MLH1 germline mutations described all along the gene that cause hereditary non-polyposis colorectal cancer (HNPCC, see below). This mutations are not present in any particular hotspot or zone of the gene and include either nucleotide substitutions (missense, nonsense or splicing errors) or insertions/deletions (gross or small). In most of these mutations the resulting protein is truncated. There are also founding mutations which account for a high proportion of the HNPCC tumours in some specific populations (for example there are two Finnish mutations that delete the exons 16 or 6). Some germline genetic changes have also been described in both exons and introns as non pathogenic.
Somatic There are described some sporadic mismatch repair deficiency cases (sporadic MSI) with somatic MLH1 mutations, although most of them have MLH1 promoter hypermetilation.

Implicated in

Entity HNPCC (Hereditary Non Polyposis Colorectal Cancer)
Disease Predisposition to develop cancer, preferentially colorectal, but also in endometrium, ovary, urinary tract, stomach, small bowel, biliary tract and brain.
Oncogenesis MLH1 mutations in HNPCC account for about 25% of the total cases approximately. This 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 been suggested that low levels of MSI characterize MLH1 and MSH2 HNPCC carriers before tumor 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 with lower incidence in some other tissues.
Prognosis MSI tumours have better prognosis than the MicroSatellite Stable (MSS).
Oncogenesis Sporadic MSI cases are mostly due to a biallelic hypermetilation of the MLH1 promotor and therefore lack of MLH1 protein expression. Few sporadic cases and about 25% of the HNPCC are due to different mutations in MLH1. 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 Inherited MLH1 mutations can cause Muir-Torre syndrome (although MSH2 mutations are more present).


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
The genetic basis of Muir-Torre syndrome includes the hMLH1 locus.
Bapat B, Xia L, Madlensky L, Mitri A, Tonin P, Narod SA, Gallinger S
American journal of human genetics. 1996 ; 59 (3) : 736-739.
PMID 8751876
Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer.
Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, Earabino C, Lipford J, Lindblom A
Nature. 1994 ; 368 (6468) : 258-261.
PMID 8145827
Microsatellite instability in inherited and sporadic neoplasms.
Eshleman JR, Markowitz SD
Current opinion in oncology. 1995 ; 7 (1) : 83-89.
PMID 7696368
DNA mismatch repair defects: role in colorectal carcinogenesis.
Jacob S, Praz F
Biochimie. 2002 ; 84 (1) : 27-47.
PMID 11900875
hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability.
Leung SY, Yuen ST, Chung LP, Chu KM, Chan AS, Ho JC
Cancer research. 1999 ; 59 (1) : 159-164.
PMID 9892201
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
Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers.
Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, Li GM, Drummond J, Modrich PL, Sedwick WD, Markowitz SD
Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (15) : 8698-8702.
PMID 9671741


This paper should be referenced as such :
Domingo, E ; Schwartz, S Jr
MLH1 (human mutL homolog 1)
Atlas Genet Cytogenet Oncol Haematol. 2005;9(2):120-122.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  Nasal T cell lymphoma (published in 2008)

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 7 ]
  Breast tumors : an overview
Colon: Colorectal adenocarcinoma
Breast: Ductal carcinoma
Gastric Tumors: an overview
Head and Neck: Oral leukoplakia
Pancreatic tumors: an overview
GOLGA4/MLH1 (3p22)

Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 3 ]
  Hereditary pancreatic cancer Lynch Syndrome Turcot syndrome

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)4292
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
Other databaseUMD-MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)). Curator: S. Olschwang
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Oct 18 17:43:47 CEST 2018

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