MLH1
protein-codingmutL homolog 1, the group of MutL homologs
Gene summary
The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
- COCA2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~57.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008315
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0010159
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0010159
Submitter: ClinGen
There is sufficient evidence published associating the MLH1 gene with constitutional mismatch repair deficiency syndrome - a distinct disorder from Lynch syndrome - since the gene-disease relationship was first proposed by Wang et al., (1999). Multiple case level studies have been performed with cMMRD patients that have variants in the MLH1 gene. Other mismatch repair (MMR) genes MSH2, MSH6 and PMS2 also causes constitutional mismatch repair deficiency syndrome. Patients' tumors and normal tissue were both negative for MLH1 protein. Multiple MLH1 deficient mouse and zebrafish models have been established to show consistent phenotypes with cMMRD patients by developing neurofibromas, lymphoma, gastrointestinal carcinoma and skin tumors. This evidence is consistent with a definitive relationship between the MLH1 gene and constitutional mismatch repair deficiency syndrome.
Inheritance Pattern: AD
Disease ID:MONDO:0016419
Submitter: ClinGen
The *MLH1* gene encodes the MLH1 protein. MLH1 protein and PMS2 protein form a heterodimer called MutLα, which is required for the DNA mismatch repair (MMR) pathway. Defective MMR pathway is responsible for microsatellite instability, a type of genomic instability that is characteristic for tumor cells. *MLH1* has been linked to Lynch Syndrome (autosomal dominant) and mismatch repair cancer syndrome (autosomal recessive), which were curated separately. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, curations to refute or dispute can be split when needed. This curation focuses on refuting the association with breast cancer. Evidence curated in this gene-disease relationship includes case-control data. **Summary of Case-Control Data: 0 point** This gene-disease relationship has been studied in at least 3 case-control studies at the aggregate variant level. In 2021, a large case-control study [BCAC (PMID: 33471991) with more than 48 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in *MLH1* and breast cancer. Likewise, another two large case-control studies published in 2017 screened breast cancer cases from commercial laboratories and did not find significant association of pathogenic mutations in *MLH1* with breast cancer (PMID: 28418444, 35172496). **Overall Summary:** In summary, given the lack of significant association in large breast cancer case-control studies to date, and lack of experimental evidence, there is convincing evidence refuting the association between *MLH1* and autosomal dominant hereditary breast cancer. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP on 6/14/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 6/9/2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0005835
Submitter: ClinGen
Lynch syndrome [MONDO:0005835], also known as Hereditary Nonpolyposis Colon Cancer [HNPCC, MONDO:0018630], is a group of autosomal dominant cancer predisposing syndrome. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra- colonic tumors of the gastrointestinal, urological and female reproductive tracts. MLH1 has been linked to Lynch Syndrome, or HNPCC in the early 1990s (PMID: 8072530). Of note, this gene has also been implicated in autosomal recessive mismatch repair cancer syndrome 1 (MONDO:0010159), which has been assessed separately due to the difference in inheritance pattern and cancer phenotype. The MLH1 gene encodes the MLH1 protein. MLH1 protein and PMS2 protein form a heterodimer called MutLα, which is required for the DNA mismatch repair (MMR) pathway. Defective MMR pathway is responsible for microsatellite instability, a type of genomic instability that is characteristic for tumor cells. Heterozygous loss of function variants in MLH1 gene have been repetitively reported in colon cancer families and individuals from various populations. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Ten loss of function variants in this gene reported in 10 probands from 10 families in 3 publications (PMIDs: 18566915, 24802709 and 33335961) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is also supported by expression, functional studies (6 points) given MLH1’s critical role in efficient mismatch repair and mouse models. (PMIDs: 24802709, 8673133 and 10096563). Mice with a Mlh1 null variant developed gastrointestinal (GI) and extra-GI tumors with microsatellite instability-high status. Mlh1-deficiency also resulted in an elevated level of CA-repeat mutation in spleen DNA. In summary, MLH1 is definitively associated with autosomal dominant Lynch syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0010159
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008018
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0010159
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008018
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007356
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0009831
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0005212
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0005835
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008018
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008170
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0012249
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0010159
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0005835
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012249
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007254
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Dermatologic; Oncologic
Intervention: Oncologic
Rationale: In HNPCC, for surveillance, colonoscopy with polyp removal is indicated starting at (whichever is earlier) age 20-25 years or 10 years prior to the earliest familial diagnosis; Prophylactic Hysterectomy with bilateral oophorectomy may be considered after childbearing is completed; For individuals with colon cancer, surgical treatment with full colectomy (and ileorectal anastomosis) is recommended; Cigarette smoking should be avoided; For other tumor types (indiviudals may be at risk for a number of cancer types), awareness of cancer risk may allow early diagnosis and treatment, which may reduce morbidity and mortality; Individuals with Mismatch repair cancer syndrome are at risk of multiple types of malignancy, and awareness may allow early detection and management
Comments: Individuals may be at risk for a number of types of cancer; Variants may also contribute to cancer susceptibility in the general population
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MLH1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000249.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 19 | 9 | 18 | 755 | 75 | 876 |
| missense | 111 | 206 | 1933 | 139 | 21 | 2410 |
| nonsense | 255 | 14 | 4 | 1 | 274 | |
| start loss | 11 | 3 | 14 | |||
| frameshift | 958 | 130 | 10 | 2 | 1100 | |
| splice donor/acceptor (+/-2bp) | 157 | 183 | 10 | 1 | 351 | |
| Total | 1511 | 545 | 1975 | 898 | 96 | 5025 |
Highest pathogenic variant AF is 0.0006357896
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000240.1 | 19 | MANE Select | |
| Ensembl | ENSP00000231790.3 | 19 | MANE Select | |
| RefSeq | NP_001161089.1 | 17 | Standard | |
| RefSeq | NP_001161090.1 | 11 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| mlh1 | Danio rerio | Structure: spermatogonium Quality: increased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Fanconi anemia pathway - Homo sapiens (human)
- Gastric cancer - Homo sapiens (human)
- Doxorubicin Pathway (Cancer Cell), Pharmacodynamics
- Mismatch repair - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
Biological Process
- nuclear-transcribed mRNA poly(A) tail shortening
- resolution of meiotic recombination intermediates
- mismatch repair
- double-strand break repair via nonhomologous end joining
- male meiosis chromosome segregation
Molecular Function
- chromatin binding
- single-stranded DNA binding
- protein binding
- ATP binding
- ATPase activity
Cellular Component
- synaptonemal complex
- male germ cell nucleus
- nucleus
- nucleoplasm
- chiasma
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000231790
- Coding exons
- 19
- Length
- 72558
- Individuals with no LoFs
- 125725
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 23
- Defined
- 125748
- p
- 0.0000915
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.304 | 413 | 396 | 1.04 | 0.0000207 | 4960 |
| Missense (PolyPhen) | 128 | 132.45 | 0.96639 | 1665 | ||
| Synonymous | -0.825 | 159 | 146 | 1.09 | 0.00000752 | 1444 |
| Loss of Function | 3.68 | 15 | 40.2 | 0.373 | 0.00000203 | 503 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.000062 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00011 | 0.00011 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS- heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis. {ECO:0000269|PubMed:16873062, ECO:0000269|PubMed:18206974, ECO:0000269|PubMed:20020535, ECO:0000269|PubMed:21120944, ECO:0000269|PubMed:9311737}.;
- Disease
- DISEASE: Mismatch repair cancer syndrome (MMRCS) [MIM:276300]: An autosomal recessive, rare, childhood cancer predisposition syndrome encompassing a broad tumor spectrum. This includes hematological malignancies, central nervous system tumors, Lynch syndrome-associated malignancies such as colorectal tumors as well as multiple intestinal polyps, embryonic tumors and rhabdomyosarcoma. Multiple cafe-au-lait macules, a feature reminiscent of neurofibromatosis type 1, are often found as first manifestation of the underlying cancer. Areas of skin hypopigmentation have also been reported in MMRCS patients. {ECO:0000269|PubMed:11427529, ECO:0000269|PubMed:17440981, ECO:0000269|PubMed:7661930}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muir-Torre syndrome (MRTES) [MIM:158320]: Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy. {ECO:0000269|PubMed:8751876}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast.; DISEASE: Endometrial cancer (ENDMC) [MIM:608089]: A malignancy of endometrium, the mucous lining of the uterus. Most endometrial cancers are adenocarcinomas, cancers that begin in cells that make and release mucus and other fluids. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Note=Some epigenetic changes can be transmitted unchanged through the germline (termed 'epigenetic inheritance'). Evidence that this mechanism occurs in humans is provided by the identification of individuals in whom 1 allele of the MLH1 gene is epigenetically silenced throughout the soma (implying a germline event). These individuals are affected by HNPCC but does not have identifiable mutations in MLH1, even though it is silenced, which demonstrates that an epimutation can phenocopy a genetic disease.; DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:10598809, ECO:0000269|PubMed:10882759, ECO:0000269|PubMed:12132870, ECO:0000269|PubMed:12655564, ECO:0000269|PubMed:14504054, ECO:0000269|PubMed:15184898, ECO:0000269|PubMed:18033691, ECO:0000269|PubMed:8872463, ECO:0000269|PubMed:9032648, ECO:0000269|PubMed:9087566, ECO:0000269|PubMed:9611074}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.882
Intolerance Scores
- LoFtool
- 0.00165
- RVIS EVS
- 0.51
- RVIS percentile EVS
- 80.3
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.881
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |