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MLH1
mutL homolog 1
The *MLH1* gene provides instructions for a protein essential in DNA mismatch repair, a crucial process that corrects errors occurring during DNA replication to maintain genomic integrity. The *MLH1* gene is a key component of the DNA mismatch repair (MMR) system.
MLH1 is located on the short (p) arm of chromosome 3, at band 3p22.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The *MLH1* gene, or mutL homolog 1, plays a fundamental role in maintaining the stability of the human genome. It encodes a protein that is an integral part of the DNA mismatch repair (MMR) pathway, a critical cellular mechanism for correcting errors that arise during DNA replication. These replication errors, if left uncorrected, can lead to mutations and potentially contribute to the development of various diseases, including cancer.
Functionally, the *MLH1* protein collaborates with other proteins to form complexes that recognise and repair mismatched DNA bases and small insertions or deletions. This intricate repair process ensures that newly synthesised DNA strands are faithful copies of the original template. Inherited pathogenic variants in the *MLH1* gene are a significant cause of Lynch syndrome, an autosomal dominant disorder characterised by a substantially elevated risk of developing several types of cancer, particularly colorectal and endometrial cancers. Additionally, biallelic pathogenic variants can lead to a more severe, early-onset condition known as constitutional mismatch repair deficiency (CMMRD).
What the gene does
The *MLH1* gene provides the blueprint for a protein that is a central component of the DNA mismatch repair (MMR) system. During DNA replication, errors can occur, leading to incorrectly paired bases or small loops of extra DNA. The primary function of the *MLH1* protein is to recognise and facilitate the correction of these errors, thus preserving the accuracy of the genetic code.
The *MLH1* protein typically forms a heterodimer with the PMS2 protein, creating a complex known as MutLα. This MutLα complex is crucial for coordinating the activities of other proteins involved in the MMR pathway. Specifically, after an initial recognition of a mismatch by another protein complex (MutSα, formed by MSH2 and MSH6, or MutSβ, formed by MSH2 and MSH3), the MutLα complex is recruited to the site of the error. MutLα acts as an endonuclease activator, promoting the excision of the erroneous DNA segment. It helps to direct exonucleases, such as EXO1, to remove the segment containing the mismatch.
Once the incorrect DNA segment is removed, DNA polymerase then synthesises a new, corrected strand, and DNA ligase seals the nicks in the DNA backbone, completing the repair process. The *MLH1* protein can also form dimers with MLH3 or PMS1, though the precise functions of these alternative complexes are not as thoroughly understood as that of MutLα. Essentially, *MLH1* acts as a key orchestrator in detecting and remedying DNA replication mistakes, thereby preventing the accumulation of mutations that could otherwise lead to genomic instability and disease.
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Chromosome location
The *MLH1* gene is situated on the short (p) arm of chromosome 3 at position 22.2, a location officially designated as 3p22.2. This specific genomic address places *MLH1* within the third chromosome, providing its precise molecular mapping within the human genome. The gene spans approximately 64,800 base pairs, from position 36,994,374 to 37,059,170 on the GRCh38.p14 assembly of the human reference genome. The *MLH1* gene is composed of 19 exons.
Protein structure
The *MLH1* protein comprises 756 amino acids and exhibits a multi-domain structure crucial for its role in DNA mismatch repair. A significant portion of the protein's conformational flexibility is attributed to two identified Disordered (Region) segments. One disordered region is located between amino acids 355-378, and another, more extended disordered region, spans from amino acids 400-491. These flexible regions may facilitate interactions with various protein partners and DNA substrates during the repair process.
An important functional area is the Interaction with EXO1 (Region), found between amino acids 410-650. This region mediates the critical binding to exonuclease 1 (EXO1), an enzyme responsible for excising the faulty DNA segment during mismatch repair. Additionally, the *MLH1* protein contains a Nuclear localization signal (Motif) at amino acids 471-474, which directs the protein to the nucleus, where DNA replication and repair processes take place.
Key variants
Variants within the *MLH1* gene encompass a spectrum of genetic changes, ranging from single base pair substitutions to larger deletions or duplications. Pathogenic variants in *MLH1* can disrupt the protein's ability to correctly participate in DNA mismatch repair, leading to an accumulation of errors in the genome. The functional impact of a variant often depends on its location within the gene and how it alters the protein's structure or its interaction with other components of the MMR pathway. Some variants may result in a non-functional protein, while others might only partially impair its activity. The classification of *MLH1* variants, typically as benign, likely benign, uncertain significance, likely pathogenic, or pathogenic, is essential for clinical interpretation and risk assessment.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.(?_-198)_207+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-198)_306+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.1039-?_(*193_?)del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-198)_116+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-198)_1558+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-198)_(*193_?)del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-198)_545+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.(?_-198)_884+?del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.-381_207+606del | - | Pathogenic | ★★★☆ | Lynch syndrome |
c.-54519_1731+2263del | - | Pathogenic | ★★★☆ | Lynch syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the *MLH1* gene are primarily associated with inherited cancer predisposition syndromes. The most common condition linked to *MLH1* is Lynch syndrome, an autosomal dominant disorder characterised by a significantly increased lifetime risk of developing various cancers, particularly colorectal cancer and endometrial cancer. Individuals with Lynch syndrome may also be at higher risk for cancers of the stomach, ovaries, small intestine, and other organs. A more severe, early-onset condition, Constitutional mismatch repair deficiency (AR), can occur when an individual inherits pathogenic variants in both copies of the *MLH1* gene, leading to a much higher cancer risk beginning in early childhood.
Inheritance pattern
Conditions caused by pathogenic MLH1 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the *MLH1* gene is extensively recognised within the NHS Genomic Medicine Service due to its strong association with inherited cancer predisposition. It is a critical gene on multiple NHS National Genomic Test Directory panels, including "Additional findings health related" and "Additional findings health related - adult specific," highlighting its importance in secondary findings. The gene is also fundamental to cancer susceptibility panels such as "Adult solid tumours cancer susceptibility" and "Childhood solid tumours cancer susceptibility." Furthermore, *MLH1* is specifically included in panels for various pertinent cancers, including "Colorectal cancer pertinent cancer susceptibility," "Endometrial cancer pertinent cancer susceptibility," "Ovarian cancer pertinent cancer susceptibility," and "Prostate cancer pertinent cancer susceptibility," among others. Its inclusion across these panels underscores its well-established role in inherited cancer syndromes, notably for "Inherited MMR deficiency (Lynch syndrome)."
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research into the influence of lifestyle on cancer risk for individuals with *MLH1* pathogenic variants, particularly those with Lynch syndrome, suggests that certain choices may play a role in modulating risk, although these findings are often derived from general population studies and require careful interpretation for specific genetic predispositions. For instance, maintaining a healthy body weight through balanced nutrition and regular physical activity is generally associated with a reduced risk of various cancers in the general population. Some studies indicate that a diet rich in fruits, vegetables, and fibre, and low in red and processed meats, may be beneficial for colorectal cancer prevention, a primary concern in *MLH1*-associated Lynch syndrome. Limiting alcohol consumption and avoiding smoking are also widely recognised as important measures for general cancer prevention. While these lifestyle recommendations are broadly applicable, individuals with *MLH1* pathogenic variants should discuss specific risk reduction strategies with their healthcare provider, as their genetic predisposition means their baseline risk is elevated.
Supplement considerations
The role of dietary supplements in mitigating cancer risk for individuals with *MLH1* pathogenic variants, particularly those with Lynch syndrome, is an area of ongoing research and should be approached with caution. While some observational studies have explored potential associations between certain micronutrients and cancer risk in the general population, there is currently no conclusive evidence that any specific supplement can prevent cancer in individuals with *MLH1*-related conditions. For example, some research has investigated the potential impact of aspirin or calcium supplementation on colorectal cancer risk, but these findings are not universally conclusive for individuals with *MLH1* pathogenic variants and often involve specific dosing and monitoring. It is essential for individuals considering any supplement regimen to consult with a healthcare professional, as supplements can interact with medications or have unintended effects. There is no scientific consensus supporting the use of specific supplements to counteract the increased cancer risk associated with *MLH1* pathogenic variants.
Frequently asked questions
What is the primary function of the MLH1 gene?
The *MLH1* gene provides instructions for a protein that is a key component of the DNA mismatch repair (MMR) system. This system corrects errors that occur during DNA replication, helping to maintain the stability and integrity of the genome.
What conditions are associated with pathogenic MLH1 variants?
Pathogenic variants in *MLH1* are primarily associated with Lynch syndrome, an inherited condition that significantly increases the risk of various cancers, particularly colorectal and endometrial cancers. Biallelic variants can also cause Constitutional mismatch repair deficiency (CMMRD).
How does the MLH1 protein work with other proteins?
The *MLH1* protein typically forms a complex with the PMS2 protein, known as MutLα. This complex coordinates the activities of other repair proteins, such as exonucleases, to remove and replace incorrect DNA segments.
Can lifestyle changes reduce cancer risk for individuals with MLH1 variants?
While no lifestyle change can eliminate the inherited risk, maintaining a healthy weight, consuming a balanced diet rich in fruits and vegetables, limiting alcohol, and avoiding smoking are generally recommended for overall cancer prevention in the general population and may be beneficial for individuals with *MLH1* variants.
Are there any supplements that can prevent cancer for people with MLH1 variants?
Currently, there is no conclusive scientific evidence that specific dietary supplements can prevent cancer in individuals with *MLH1* pathogenic variants. Any decision to take supplements should be discussed with a healthcare professional.
Is MLH1 included in NHS genetic testing panels?
Yes, *MLH1* is included in numerous NHS National Genomic Test Directory panels, particularly those related to inherited cancer susceptibility, including specific panels for colorectal, endometrial, and ovarian cancers, and for inherited MMR deficiency (Lynch syndrome).
References
- Dominguez-Valentin M, Sampson JR, Seppälä TT. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genetics in medicine : official journal of the American College of Medical Genetics. 2020. PMID: 31337882
- Wimmer K, Kratz CP, Vasen HF. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD). Journal of medical genetics. 2014. PMID: 24737826
- Andersen SD, Liberti SE, Lützen A. Functional characterization of MLH1 missense variants identified in Lynch syndrome patients. Human mutation. 2012. PMID: 22753075
- South CD, Hampel H, Comeras I. The frequency of Muir-Torre syndrome among Lynch syndrome families. Journal of the National Cancer Institute. 2008. PMID: 18270343
- Raevaara TE, Korhonen MK, Lohi H. Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. Gastroenterology. 2005. PMID: 16083711
- Peltomäki P. Lynch syndrome genes. Familial cancer. 2005. PMID: 16136382
- Adam MP, Bick S, Mirzaa GM. Lynch Syndrome. 1993. PMID: 20301390