What you carry at this position in your DNA and what research says about it.
Colorectal Cancer Risk: 6/10 evidence, 22 publications.
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Sample genotype (not yours): G/G
Typical Colorectal Cancer Risk
This genotype is associated with typical levels of MLH1 gene expression and standard mismatch repair activity. It carries a baseline risk for colorectal cancer and typical responses to methylating chemotherapies.
What this genotype means: Typical MLH1 gene expression; Standard DNA mismatch repair activity.
Sample genotype (not yours): A/A
Increased Colorectal Cancer Risk
Carrying two copies of the A allele is associated with significantly reduced MLH1 expression and increased promoter hypermethylation. This genotype is linked to a higher risk of microsatellite instability-high colorectal cancer.
What this genotype means: Reduced MLH1 expression due to promoter hypermethylation; Increased risk of microsatellite instability-high colorectal cancer.
Sample genotype (not yours): G/A
Slightly Increased Colorectal Cancer Risk
Carrying one copy of the A allele is linked to slightly lower MLH1 expression due to promoter methylation. This leads to a modest increase in the risk of developing certain subtypes of colorectal cancer.
What this genotype means: Slightly reduced MLH1 expression; Modestly increased risk of microsatellite-unstable tumors.
Gene function and biological role
Gene Function: The MLH1 gene plays a critical role in maintaining genomic stability by encoding a protein essential for DNA mismatch repair. This repair system corrects errors that occur spontaneously during DNA replication. When MLH1 function is compromised, cells accumulate mutations rapidly, a state known as microsatellite instability [1]. Inherited mutations that completely disable MLH1 cause Lynch syndrome, which carries a very high lifetime risk of colorectal and other cancers [2]. However, common regulatory variants in the gene can also subtly influence its expression levels without causing Lynch syndrome [3].
Variant Impact: The rs1800734 variant, often referred to as -93G>A, is located in the promoter region of the MLH1 gene. The A allele is associated with increased DNA methylation at the promoter, which acts to epigenetically quiet or reduce the gene's expression [1]. This reduction in MLH1 protein levels can impair mismatch repair efficiency, making cells more prone to genomic instability [3]. While expert panels classify this variant as benign for high-risk Lynch syndrome, it acts as a low-penetrance risk factor for sporadic colorectal cancer [2]. Additionally, it has been studied for its impact on cellular sensitivity to certain chemotherapy drugs [4].
Key Insight: This variant does not cause high-risk Lynch syndrome, but it subtly alters gene expression by increasing DNA methylation, acting as a low-penetrance modifier of colorectal cancer risk.
Location: MLH1. Chromosome 3 · 3p22.2 · 37.0 Mb
Estimated prevalence by population
Global 59.6%; European 61.6%; African 68.6%; East Asian 19.8%; South Asian 38.0%; Americas 52.7%; Ashkenazi 45.1%; Finnish 56.7%; Middle Eastern 38.7%; Amish 68.9%.
Estimated GG genotype frequency.
Global 34.4%; European 33.8%; African 28.5%; East Asian 49.4%; South Asian 47.3%; Americas 39.8%; Ashkenazi 44.1%; Finnish 37.2%; Middle Eastern 47.0%; Amish 28.2%.
Estimated GA genotype frequency.
Global 6.0%; European 4.6%; African 3.0%; East Asian 30.7%; South Asian 14.7%; Americas 7.5%; Ashkenazi 10.8%; Finnish 6.1%; Middle Eastern 14.3%; Amish 2.9%.
Estimated AA genotype frequency.
Showing effects for G/G genotype
Cancer & Oncology
Colorectal Cancer
Colorectal Cancer. Evidence: 6/10. Source: PMID 33632709. Typical Risk.
Organ Systems
Liver Function & Disease
Liver Enzyme Levels. Evidence: 6/10. Source: PMID 33462484. Typical GGT.
Pharmacogenomics
Chemotherapy Response
Chemotherapy Response. Evidence: 5/10. Source: PMID 17959715. Typical Response.
Showing effects for A/A genotype
Colorectal Cancer. Evidence: 6/10. Source: PMID 33632709. Increased Risk.
Liver Enzyme Levels. Evidence: 6/10. Source: PMID 33462484. Higher GGT.
Chemotherapy Response. Evidence: 5/10. Source: PMID 17959715. Altered Sensitivity.
Showing effects for G/A genotype
Colorectal Cancer. Evidence: 6/10. Source: PMID 33632709. Slightly Increased.
Liver Enzyme Levels. Evidence: 6/10. Source: PMID 33462484. Slightly Higher GGT.
What this genotype means for the people who carry it
Sample genotype: GG (Homozygous)
Mismatch repair processes function at typical capacity with this genotype, as the promoter region lacks the methylation-inducing A allele [1]. Large-scale genetic analyses and expert panels confirm that this common genotype represents the baseline risk for hereditary cancer syndromes like Lynch syndrome [2]. Individuals with this genotype do not experience the subtle reduction in MLH1 protein levels associated with the variant allele [3]. Consequently, the risk of developing colorectal cancer remains at the average population level [4]. Additionally, standard responses are expected if treated with methylating chemotherapy agents such as dacarbazine or procarbazine [5].
Typical MLH1 gene expression; Standard DNA mismatch repair activity.
Sample genotype: AA (Homozygous)
Having two copies of the A allele is strongly associated with hypermethylation of the MLH1 promoter, which significantly dampens gene expression [1]. This reduction in MLH1 protein levels compromises the cell's ability to repair DNA replication errors, leading to microsatellite instability [2]. Clinical research has shown that this genotype is associated with an increased risk of colorectal cancer, particularly the microsatellite instability-high subtype [3]. Some studies report up to a three-fold increased risk for specific tumor characteristics, although the overall risk remains low-penetrance [4]. Furthermore, this genotype has been linked to an increased likelihood of developing secondary complications, such as breast cancer or treatment-related leukemia, following exposure to methylating chemotherapies like dacarbazine or procarbazine [5].
Reduced MLH1 expression due to promoter hypermethylation; Increased risk of microsatellite instability-high colorectal cancer.
Sample genotype: GA (Heterozygous)
Having one copy of the A allele introduces a subtle epigenetic change in the MLH1 promoter region, leading to increased DNA methylation [1]. This methylation slightly reduces the transcription of the MLH1 gene, resulting in lower levels of the mismatch repair protein [2]. While expert clinical databases classify this variant as benign for high-risk Lynch syndrome, it is recognized as a low-penetrance risk factor for sporadic colorectal cancer [3]. Studies indicate a modest increase in the likelihood of developing colorectal tumors, particularly those characterized by microsatellite instability [4]. There is also a potential, though less common, association with altered side-effect profiles when undergoing specific methylating chemotherapy treatments [5].
Slightly reduced MLH1 expression; Modestly increased risk of microsatellite-unstable tumors.
Variants with shared genetic architecture
rs111052004 · MLH1 Gene · Chr 3 · Lynch Syndrome Risk
rs11541859 · MLH1 Gene · Chr 3 · Lynch Syndrome Risk
rs1799977 · MLH1 Gene · Chr 3 · Lynch Syndrome Risk
Inheritance of a cancer-associated MLH1 germ-line epimutation.
MLH1 -93G>A promoter polymorphism and risk of mismatch repair deficient colorectal cancer.
Polymorphic MLH1 and risk of cancer after methylating chemotherapy for Hodgkin lymphoma.
Genetic architectures of proximal and distal colorectal cancer are partly distinct.
Content updated August 2026.
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