What you carry at this position in your DNA and what research says about it.
Endometrial Cancer Risk: 6/10 evidence, 59 publications.
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Sample genotype (not yours): C/C
Lower Cancer Risk but Poorer Pain Relief
Estrogen metabolism remains highly efficient, keeping the risk of endometrial cancer at baseline levels. However, standard pain medications like morphine and butorphanol may be less effective.
What this genotype means: Lower risk of endometrial cancer; Reduced response to opioid pain relief; Typical blood sugar and body mass index.
Sample genotype (not yours): C/T
Increased Cancer Risk and Altered Pain Response
Uterine tissues face a higher susceptibility to estrogen-driven changes, elevating the risk of endometrial cancer. Pain management is also affected, with a potentially reduced response to certain opioid medications.
What this genotype means: Elevated risk of endometrial cancer; Altered sensitivity and response to pain medications; Slightly higher trend for blood sugar and BMI.
Sample genotype (not yours): T/T
Higher Cancer Risk and Elevated Metabolic Markers
Reduced COMT enzyme levels elevate the risk of endometrial cancer and are associated with higher blood sugar and BMI. However, response to standard pain medications is typically more favorable.
What this genotype means: Elevated risk of endometrial cancer; Higher average blood sugar and body mass index; More favorable response to standard pain medications.
Gene function and biological role
Gene Function: Catechol-O-methyltransferase, encoded by the COMT gene, is a vital enzyme responsible for breaking down catecholamines like dopamine, epinephrine, and norepinephrine [1]. By regulating these neurotransmitters, the enzyme plays a central role in modulating pain perception, cognitive processing, and stress responses [2]. It also metabolizes catechol estrogens, converting potentially harmful estrogen byproducts into benign compounds [3]. Variations in this gene can alter enzyme activity, thereby influencing susceptibility to hormone-sensitive cancers and chronic pain conditions [4].
Variant Impact: The rs4633 variant is a synonymous change located at codon 62 of the COMT gene, meaning it does not alter the final amino acid sequence of the protein [3]. Despite being a silent mutation, this nucleotide change affects the secondary structure and folding stability of the COMT mRNA transcript [5]. These structural alterations modify how efficiently the ribosome translates the genetic code, ultimately changing COMT protein expression levels [3]. Consequently, this single-nucleotide variation influences both the clearance of dopamine in the brain and the processing of estrogens in peripheral tissues [6].
Key Insight: A silent mutation that does not change any amino acids can still alter protein levels by changing how mRNA folds.
Location: COMT. Chromosome 22 · 22q11.21 · 20.0 Mb
Estimated prevalence by population
Global 31.5%; European 23.2%; African 44.8%; East Asian 53.3%; South Asian 29.6%; Americas 35.4%; Ashkenazi 29.2%; Finnish 20.2%; Middle Eastern 28.2%; Amish 11.3%.
Estimated CC genotype frequency.
Global 47.7%; European 49.9%; African 44.2%; East Asian 39.4%; South Asian 49.6%; Americas 48.2%; Ashkenazi 49.7%; Finnish 49.5%; Middle Eastern 49.8%; Amish 44.6%.
Estimated CT genotype frequency.
Global 20.7%; European 26.9%; African 10.9%; East Asian 7.3%; South Asian 20.8%; Americas 16.4%; Ashkenazi 21.2%; Finnish 30.3%; Middle Eastern 22.0%; Amish 44.2%.
Estimated TT genotype frequency.
Showing effects for C/C genotype
Cancer & Oncology
Gynecological Cancers
Endometrial Cancer. Evidence: 3/10. Source: PMID 18324659. Typical Risk.
Pharmacogenomics
Pain Medication Response
Pain Relief Response. Evidence: 5/10. Source: PMID 31967515. Poorer Response.
Cardiovascular & Metabolic
Diabetes & Glycemic Traits
Blood Glucose. Evidence: 6/10. Source: PMID 39024449. Typical Levels.
Obesity & Body Composition
Body Mass Index. Evidence: 6/10. Source: PMID 36376304. Typical BMI.
Showing effects for C/T genotype
Endometrial Cancer. Evidence: 3/10. Source: PMID 18324659. Increased Risk.
Pain Relief Response. Evidence: 5/10. Source: PMID 31967515. Reduced Response.
Blood Glucose. Evidence: 6/10. Source: PMID 39024449. Slightly Higher.
Body Mass Index. Evidence: 6/10. Source: PMID 36376304. Slightly Higher.
Showing effects for T/T genotype
Pain Relief Response. Evidence: 5/10. Source: PMID 31967515. Typical Response.
Blood Glucose. Evidence: 6/10. Source: PMID 39024449. Higher Levels.
Body Mass Index. Evidence: 6/10. Source: PMID 36376304. Higher BMI.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Efficient clearance of catechol estrogens helps protect uterine tissues from DNA-damaging estrogen byproducts, maintaining a typical risk profile for endometrial cancer [1]. In contrast, the enzymatic activity associated with this genotype alters the processing of catecholamines, which can heighten sensitivity to physical pain [2]. Clinical studies indicate that standard doses of opioids, such as morphine and butorphanol, often provide suboptimal pain relief [3]. Patients undergoing surgery or managing chronic pain may respond less strongly to pain medication, so alternative strategies may be considered [4]. Additionally, this genetic profile is linked to typical blood sugar levels and a standard body mass index [5]. Dopamine clearance in the prefrontal cortex remains balanced, supporting typical executive function and cognitive performance [6].
Lower risk of endometrial cancer; Reduced response to opioid pain relief; Typical blood sugar and body mass index.
Sample genotype: CT (Heterozygous)
Altered mRNA stability leads to reduced expression of the COMT enzyme, which impairs the breakdown of potentially carcinogenic catechol estrogens [1]. This metabolic shift is associated with a significantly higher risk of developing endometrial cancer [1]. Neurotransmitter clearance is also affected, leading to variations in how the nervous system processes pain signals [2]. Standard pain therapies, including morphine, may show reduced efficacy for acute discomfort [3]. Metabolic markers show a slight trend toward higher blood sugar levels and body mass index [4]. Cognitive processing and executive function remain largely typical, though subtle differences in dopamine-dependent tasks have been observed [5].
Elevated risk of endometrial cancer; Altered sensitivity and response to pain medications; Slightly higher trend for blood sugar and BMI.
Sample genotype: TT (Homozygous)
Uterine tissue exposure to DNA-damaging estrogen intermediates is increased due to lower COMT expression, elevating endometrial cancer risk [1]. This genotype is also linked to higher average blood sugar levels, as measured by HbA1c, and an increased body mass index [2] [3]. Dopamine clearance in the brain is altered, which can impact executive function and cognitive performance under certain conditions [4]. On the positive side, pain processing pathways are modulated in a way that typically allows for better pain tolerance [5]. Standard pain medications, including opioids like morphine, generally provide more effective relief at typical doses compared to other genotypes [6]. Propranolol therapy for chronic pain may also be more effective, with fewer reports of severe pain during treatment [7].
Elevated risk of endometrial cancer; Higher average blood sugar and body mass index; More favorable response to standard pain medications.
Variants with shared genetic architecture
rs165722 · COMT Gene · Chr 22 · Opioid Nausea Risk
rs4680 · COMT Gene · Chr 22 · Stress and Focus
rs165599 · COMT Gene · Chr 22 · Mental Health Risk
COMT polymorphisms affecting protein expression are risk factors for endometrial cancer.
Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
Catechol-o-methyltransferase gene and executive function in children with ADHD.
Pleiotropic genetic architecture and novel loci for C-reactive protein levels.
Content updated August 2026.
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