MLH1
mutL homolog 1, the group of MutL homologs
Basic information
Region (hg38): 3:36993226-37050896
Previous symbols: [ "COCA2" ]
Links
Phenotypes
GenCC
Source:
- rhabdomyosarcoma (Moderate), mode of inheritance: AR
- Lynch syndrome 2 (Strong), mode of inheritance: AD
- ovarian cancer (Strong), mode of inheritance: AD
- malignant pancreatic neoplasm (Moderate), mode of inheritance: AD
- Muir-Torre syndrome (Strong), mode of inheritance: AD
- Muir-Torre syndrome (Moderate), mode of inheritance: AD
- mismatch repair cancer syndrome 1 (Definitive), mode of inheritance: AR
- Lynch syndrome 2 (Definitive), mode of inheritance: AD
- Muir-Torre syndrome (Supportive), mode of inheritance: AD
- Lynch syndrome (Supportive), mode of inheritance: AD
- mismatch repair cancer syndrome 1 (Supportive), mode of inheritance: AR
- breast cancer (Disputed Evidence), mode of inheritance: AD
- prostate cancer (Limited), mode of inheritance: AD
- Muir-Torre syndrome (Definitive), mode of inheritance: AD
- mismatch repair cancer syndrome 1 (Definitive), mode of inheritance: AR
- mismatch repair cancer syndrome 1 (Strong), mode of inheritance: AR
- Lynch syndrome 1 (Strong), mode of inheritance: AD
- Lynch syndrome (Definitive), mode of inheritance: AD
- mismatch repair cancer syndrome 1 (Definitive), mode of inheritance: AR
- hereditary breast carcinoma (Refuted Evidence), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Colorectal cancer, hereditary nonpolyposis, type 2 (Lynch syndrome 2); Mismatch repair cancer syndrome 1; Endometrial cancer; Muir-Torre syndrome | AD/AR | Oncologic | 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 | Dermatologic; Oncologic | 6020987; 5684233; 4063166; 7815421; 8128251; 8145827; 7661930; 8751876; 9634524; 9927033; 10072435; 10577927; 15264268; 15077197; 16042583; 15520370; 15662714; 15235030; 17440981; 18457354; 19156169; 20301390; 24434690 |
| Individuals may be at risk for a number of types of cancer; Variants may also contribute to cancer susceptibility in the general population |
ClinVar
This is a list of variants' phenotypes submitted to
- Hereditary cancer-predisposing syndrome (707 variants)
- Colorectal cancer, hereditary nonpolyposis, type 2 (595 variants)
- Hereditary nonpolyposis colorectal neoplasms (469 variants)
- Lynch syndrome (454 variants)
- not provided (202 variants)
- Lynch syndrome 1 (57 variants)
- Hereditary nonpolyposis colon cancer (35 variants)
- Carcinoma of colon (29 variants)
- Lynch-like syndrome (27 variants)
- Gastric cancer (7 variants)
- Colon cancer (6 variants)
- Mismatch repair cancer syndrome 1 (6 variants)
- Muir-Torré syndrome (5 variants)
- Mismatch repair cancer syndrome 1;Muir-Torré syndrome;Colorectal cancer, hereditary nonpolyposis, type 2 (5 variants)
- Breast and/or ovarian cancer (4 variants)
- Endometrial carcinoma (4 variants)
- MLH1-related disorder (3 variants)
- See cases (2 variants)
- Colorectal cancer, hereditary nonpolyposis, type 2;Mismatch repair cancer syndrome 1;Muir-Torré syndrome (2 variants)
- Colonic neoplasm (2 variants)
- not specified (1 variants)
- Colorectal cancer, hereditary nonpolyposis, type 2;Muir-Torré syndrome (1 variants)
- Breast carcinoma (1 variants)
- Muir-Torré syndrome;Mismatch repair cancer syndrome 1;Colorectal cancer, hereditary nonpolyposis, type 2 (1 variants)
- Inherited MMR deficiency (Lynch syndrome) (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the MLH1 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 10 | 558 | 572 | |||
| missense | 63 | 97 | 1551 | 56 | 19 | 1786 |
| nonsense | 233 | 11 | 253 | |||
| start loss | 12 | |||||
| frameshift | 805 | 81 | 891 | |||
| inframe indel | 12 | 15 | 53 | 80 | ||
| splice donor/acceptor (+/-2bp) | 73 | 143 | 216 | |||
| splice region | 40 | 49 | 116 | 112 | 22 | 339 |
| non coding | 18 | 15 | 249 | 457 | 71 | 810 |
| Total | 1211 | 366 | 1877 | 1073 | 93 |
Highest pathogenic variant AF is 0.0000131
Variants in MLH1
This is a list of pathogenic ClinVar variants found in the MLH1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 3-36993228-G-C | Hereditary cancer-predisposing syndrome | Uncertain significance (Jul 15, 2016) | ||
| 3-36993240-G-A | Hereditary cancer-predisposing syndrome | Uncertain significance (May 18, 2018) | ||
| 3-36993241-T-A | Hereditary cancer-predisposing syndrome | Uncertain significance (May 26, 2016) | ||
| 3-36993244-T-A | Hereditary cancer-predisposing syndrome | Uncertain significance (Aug 25, 2016) | ||
| 3-36993244-TCCCCGAGCTCCTAAAAACGAA-T | Hereditary cancer-predisposing syndrome | Uncertain significance (Sep 16, 2019) | ||
| 3-36993245-C-T | Hereditary cancer-predisposing syndrome | Uncertain significance (Apr 17, 2019) | ||
| 3-36993246-C-A | Hereditary cancer-predisposing syndrome | Uncertain significance (Feb 04, 2020) | ||
| 3-36993246-C-T | Hereditary cancer-predisposing syndrome | Uncertain significance (May 01, 2019) | ||
| 3-36993247-C-T | Hereditary cancer-predisposing syndrome | Uncertain significance (Oct 11, 2017) | ||
| 3-36993248-C-G | Hereditary cancer-predisposing syndrome | Uncertain significance (Aug 28, 2019) | ||
| 3-36993249-G-A | Hereditary cancer-predisposing syndrome | Uncertain significance (Aug 14, 2018) | ||
| 3-36993250-A-G | Hereditary cancer-predisposing syndrome | Uncertain significance (Apr 03, 2017) | ||
| 3-36993253-T-A | Hereditary cancer-predisposing syndrome | Uncertain significance (Apr 02, 2020) | ||
| 3-36993254-C-G | Hereditary cancer-predisposing syndrome | Uncertain significance (Apr 20, 2020) | ||
| 3-36993255-C-T | Hereditary cancer-predisposing syndrome | Uncertain significance (Sep 27, 2018) | ||
| 3-36993256-TA-T | Hereditary cancer-predisposing syndrome | Uncertain significance (Sep 27, 2018) | ||
| 3-36993260-A-G | Hereditary cancer-predisposing syndrome | Uncertain significance (Mar 10, 2014) | ||
| 3-36993262-C-T | Hereditary cancer-predisposing syndrome | Uncertain significance (Jul 22, 2019) | ||
| 3-36993263-G-A | Hereditary cancer-predisposing syndrome | Uncertain significance (Sep 09, 2019) | ||
| 3-36993263-G-C | Hereditary cancer-predisposing syndrome | Uncertain significance (Apr 16, 2018) | ||
| 3-36993263-G-T | Hereditary cancer-predisposing syndrome | Uncertain significance (Aug 19, 2019) | ||
| 3-36993267-CAATAGGAAGAGCG-C | Hereditary cancer-predisposing syndrome | Uncertain significance (Nov 30, 2018) | ||
| 3-36993268-A-G | Hereditary cancer-predisposing syndrome | Uncertain significance (Dec 19, 2019) | ||
| 3-36993269-A-G | Hereditary cancer-predisposing syndrome | Uncertain significance (Feb 21, 2019) | ||
| 3-36993274-A-C | Hereditary cancer-predisposing syndrome | Uncertain significance (Mar 04, 2019) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| MLH1 | protein_coding | protein_coding | ENST00000231790 | 19 | 72558 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.0000341 | 1.00 | 125725 | 0 | 23 | 125748 | 0.0000915 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | -0.304 | 413 | 396 | 1.04 | 0.0000207 | 4960 |
| Missense in 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 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000210 | 0.000148 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.000115 | 0.000114 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.000163 | 0.000163 |
| Other | 0.000163 | 0.000163 |
dbNSFP
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.;
- Pathway
- 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);Busulfan Pathway, Pharmacodynamics;Endometrial cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);Ovarian Infertility Genes;TP53 Regulates Transcription of DNA Repair Genes;Chromosomal and microsatellite instability in colorectal cancer;Mismatch repair;Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta);Mismatch Repair;DNA Repair;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;TP53 Regulates Transcription of DNA Repair Genes;Transcriptional Regulation by TP53;Direct p53 effectors;Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)
(Consensus)
Recessive Scores
- pRec
- 0.882
Intolerance Scores
- loftool
- 0.00165
- rvis_EVS
- 0.51
- rvis_percentile_EVS
- 80.3
Haploinsufficiency Scores
- pHI
- 0.713
- hipred
- Y
- hipred_score
- 0.651
- ghis
- 0.510
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.881
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Mlh1
- Phenotype
- integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype; vision/eye phenotype; hematopoietic system phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); neoplasm; respiratory system phenotype; immune system phenotype; digestive/alimentary phenotype;
Zebrafish Information Network
- Gene name
- mlh1
- Affected structure
- spermatogonium
- Phenotype tag
- abnormal
- Phenotype quality
- increased amount
Gene ontology
- 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;synapsis;spermatogenesis;intrinsic apoptotic signaling pathway in response to DNA damage;response to bacterium;female meiosis chromosome segregation;somatic hypermutation of immunoglobulin genes;meiotic metaphase I plate congression;meiotic telomere clustering;isotype switching;negative regulation of mitotic recombination;positive regulation of isotype switching to IgA isotypes;positive regulation of isotype switching to IgG isotypes;oogenesis;meiotic spindle midzone assembly
- Cellular component
- synaptonemal complex;male germ cell nucleus;nucleus;nucleoplasm;chiasma;late recombination nodule;membrane;mismatch repair complex;MutLalpha complex
- Molecular function
- chromatin binding;single-stranded DNA binding;protein binding;ATP binding;ATPase activity;enzyme binding;guanine/thymine mispair binding;MutSalpha complex binding