rs2736100
badMag 6.0This is a intron variant variant in the TERT gene.
Key Literature Trait Associations
Myeloproliferative neoplasm
The C allele at rs2736100 confers substantially elevated risk for myeloproliferative neoplasms (MPNs), a group of clonal hematopoietic disorders including polycythemia vera, essential thrombocythemia, and myelofibrosis. A meta-analysis by Hong et al. (2020, 3,488 cases and 57,948 controls) found homozygous CC carriers have OR=3.00 compared to AA homozygotes (per-allele OR=1.57, p<0.001). This is among the largest common-variant effect sizes observed for any hematologic malignancy. Evidence also suggests the C allele interacts synergistically with the JAK2 V617F somatic driver mutation to further increase MPN risk.
Idiopathic pulmonary fibrosis
In contrast to its cancer associations, the A allele (associated with shorter telomeres) at rs2736100 increases risk for idiopathic pulmonary fibrosis (IPF), a progressive fibrotic lung disease strongly linked to telomere dysfunction. The Fingerlin et al. 2013 GWAS confirmed the TERT locus at 5p15 as a significant IPF susceptibility locus. A 2024 meta-analysis (Singh et al.) reported OR=0.68 for the C allele (i.e., A allele OR≈1.47), consistent with the known biology whereby telomere shortening in alveolar epithelial cells drives fibrosis. This inverse relationship to the cancer risk allele exemplifies the dual role of telomere maintenance in human disease.
Lung Cancer Risk (Adenocarcinoma)
The rs2736100 variant in intron 2 of TERT (telomerase reverse transcriptase) on chromosome 5p15.33 is a confirmed risk factor for lung adenocarcinoma. A meta-analysis of 56,223 cases and 86,680 controls found the C allele increases risk with a per-allele OR of 1.20. The C allele upregulates TERT expression, maintaining telomere length but also promoting cancer cell immortalization. This variant also shows associations with thyroid cancer, bladder cancer, and glioma.
Testicular germ cell tumor
The T allele (complement of C on the plus-strand convention used in some papers) at rs2736100 is strongly associated with increased testicular germ cell tumor (TGCT) risk. The UK Testicular Cancer Collaboration GWAS (Turnbull et al. 2010, n=9,046 combined) identified rs2736100 within the TERT-CLPTM1L locus with OR=1.33 and p=7.55×10⁻¹⁵, establishing it as one of the strongest common-variant TGCT susceptibility loci. The association was independently validated in a pediatric germ cell tumor cohort (Cigan et al. 2022), where the same variant reached p=0.0003, underscoring its shared biology across age groups.
Overall cancer risk
Across 69 studies encompassing 75,274 cancer cases and 103,248 controls, the C allele at rs2736100 is associated with increased risk for multiple cancer types including thyroid cancer, bladder cancer, glioma, and lung cancer, in addition to MPNs. The 2017 meta-analysis by Li et al. (108,248 cases, 161,472 controls) found homozygous GG (equivalent C-allele notation) vs. TT OR=1.39 across all cancers, though the effect is heterogeneous across tumor types. Notably, the C allele shows decreased risk for breast cancer and colorectal cancer, highlighting the complex, context-dependent role of telomere length in carcinogenesis.
Telomere Length
The C allele of rs2736100 in TERT is associated with longer telomere length in blood cells, adding approximately 67 base pairs per copy. Paradoxically, the same C allele that increases telomere length also increases lung cancer risk, likely because enhanced telomere maintenance promotes both cellular longevity and cancer cell immortalization. This variant illustrates the complex role of telomere biology in aging and cancer.
Erythrocyte count
The C allele at rs2736100 is associated with modestly higher erythrocyte (red blood cell) count in large GWAS of hematological traits, with beta=0.067 SD units and p=3×10⁻⁸ as reported in the GWAS Catalog. This hematological effect may partially reflect the same telomerase biology driving MPN susceptibility — elevated telomerase activity in hematopoietic progenitors supports increased red cell production. The effect size is modest and its direct clinical significance in the general population is limited.
▶GWAS Catalog Trait Associations (25)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (25)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶ClinVar annotation
Chronic obstructive pulmonary disease; Chronic osteomyelitis; Combined pulmonary fibrosis-emphysema syndrome; Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis; Interstitial lung disease 2 (ILD2); Susceptibility to severe coronavirus disease (COVID-19)
View on ClinVar →▶Research that mentions this SNP (18)
▶Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA studyAssociationN=6,700Campa D. et al.(2019)· International Journal of Cancer
This case-control association study analyzed 10 telomere-length-associated SNPs in relation to pancreatic cancer risk in 2,374 cases and 4,326 controls from the PANDoRA consortium. The strongest association was with TERT-rs2736100 (OR=1.54, p=1.54×10⁻¹⁰), and a novel protective association was found with NAF1-rs7675998 (OR=0.80, p=1.87×10⁻⁶). A genetic telomere length score (teloscore) combining these variants reached genome-wide significance for PDAC risk (p=2.98×10⁻⁹ for highest vs. lowest quintile).
▶ATG12 expression quantitative trait loci associated with head and neck squamous cell carcinoma risk in a Chinese Han populationAssociationN=1,056Xueyao Song et al.(2018)· Molecular Carcinogenesis
This study investigated the association of MGMT enhancer variant rs11016629 with glioma susceptibility and progression in 402 patients and 654 controls. The TG genotype was associated with increased glioma risk (OR=1.41, 95% CI 1.03-1.93, P=0.034), particularly in WHO grade IV tumors (OR=1.59, P=0.023). In patients who underwent gross total resection, carriers with TG/TT genotypes had worse progression-free survival (HR=2.66, 95% CI 1.23-5.79, P=0.014) compared to GG carriers.
▶Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors: A report from the children's oncology groupAssociationN=366Marcotte EL et al.(2017)· Genes, Chromosomes and Cancer
Case-parent triad study of 366 pediatric and adolescent germ cell tumor (GCT) cases examining 26 SNPs from adult testicular GCT GWAS. Three variants reached multiple testing-corrected significance: SPRY4 rs4624820 (OR=0.70, protective), BAK1 rs210138 (OR=1.70, particularly strong for testicular tumors OR=3.31), and GAB2 rs948662 (OR=1.56). Maternal effects observed for KITLG rs4474514 (OR=1.66) and rs7221274 near TEX14/RAD51C/PPM1E (OR=1.63).
▶Case–Control Study on Impact of the Telomerase Reverse Transcriptase Gene Polymorphism and Additional Single Nucleotide Polymorphism (SNP)– SNP Interaction on Non‐Small Cell Lung Cancers Risk in Chinese Han PopulationAssociationN=828Yan‐li Xing et al.(2016)· Journal of Clinical Laboratory Analysis
Case-control study of 828 Chinese Han participants (410 NSCLC cases, 418 controls) examining TERT gene polymorphisms and their SNP-SNP interactions on non-small cell lung cancer risk. Carriers of the G allele at rs2736100 showed increased NSCLC risk (OR=1.68, 95% CI: 1.28-2.07), as did carriers of the A allele at rs2736098 (OR=1.52, 95% CI: 1.19-1.93). A significant gene-gene interaction was found between rs2736098 and rs2736100 (OR=2.52, 95% CI: 1.68-3.68 for GA/AA and TG/GG combined genotypes versus reference).
▶Effect of CDKN2A/B rs4977756 polymorphism on glioma risk: a meta-analysis of 16 studies including 24077 participantsMeta-analysisN=23,987Xuchen Qi et al.(2016)· Mammalian Genome
A meta-analysis of 16 studies (8,129 cases, 15,858 controls) examined the association between CDKN2A/B rs4977756 polymorphism and glioma risk. The G allele was associated with increased glioma risk across multiple inheritance models in Caucasians (dominant model: OR=1.36, 95% CI=1.20-1.54; homozygous GG: OR=1.49, 95% CI=1.36-1.64), but no association was found in Asian populations. Results support rs4977756 as a glioma susceptibility locus, particularly in European ancestry populations.
▶Telomere structure and maintenance gene variants and risk of five cancer typesMeta-analysisN=136,308Sara Karami et al.(2016)· International Journal of Cancer
Meta-analysis of 204,993 SNPs in 22 telomere structure and maintenance genes identified 13 independent SNPs associated with colorectal, breast, prostate, ovarian, and lung cancer risk in 61,851 cases and 74,457 controls of European descent. Seven of these associations were novel findings. Notable findings include rs12655062 (positively associated with prostate cancer, inversely with colorectal/ovarian cancers), rs75316749 (positively associated with colorectal, breast, ovarian, and lung cancers), rs974404 and rs12144215 in DCLRE1B (inversely associated with prostate/lung and colorectal/breast/ovarian cancers respectively), rs34978822 in RTEL1 (inversely associated with prostate/lung cancers), and rs116895242 near POT1 (inversely associated with colorectal, ovarian, and lung cancers).
▶Association of human telomerase reverse transcriptase gene polymorphisms, serum levels, and telomere length with renal cell carcinoma risk and pathologyMeta-analysisN=269,720Michela de Martino et al.(2016)· Molecular Carcinogenesis
A meta-analysis of 72 studies comprising 108,248 cases and 161,472 controls found that the TERT rs2736100 T>G polymorphism increases overall cancer risk by 16-39% (OR = 1.17-1.39 across genetic models). Stratified analysis showed strongest associations with lung cancer (OR = 1.24-1.60), and also elevated risk for thyroid cancer, bladder cancer, glioma, myeloproliferative neoplasms, and acute myeloid leukemia, with decreased colorectal cancer risk.
▶Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controlsAssociationN=21,152Darren R. Brenner et al.(2013)· Human Genetics
Two-stage GWAS of 10,140 lung cancer cases and 11,012 controls in inflammation pathways using hierarchical modeling identified one novel locus at rs2741354 in EPHX2 (p=7.4×10⁻⁶), and confirmed associations with TERT (rs2736100) and HLA region variants. Hierarchical modeling incorporating prior biological knowledge identified 32 replicated variants not captured by conventional maximum likelihood analysis.
▶Telomere length, telomere‐related genes, and breast cancer risk: The breast cancer health disparities studyAssociationN=8,123Andrew J. Pellatt et al.(2013)· Genes, Chromosomes and Cancer
This case-control study of 3,754 breast cancer cases and 4,369 controls from admixed US and Mexican women examined telomere length (TL) and nine telomere-related genes. Longer TL was associated with increased breast cancer risk (OR 1.87, 95% CI 1.38-2.55), with strongest association among women with ≥70% Indigenous American ancestry (OR 3.11, 95% CI 1.74-5.67). Multiple SNPs showed associations with breast cancer risk, including TEP1 rs938886 (OR 0.82), TERT rs4246742 (OR 0.85), TERT rs2242652 (OR 1.51), TERF2 rs3785074 (OR 1.13), and TNKS rs6990300 (OR 0.89). Several SNPs showed differential associations by hormone receptor status and genetic ancestry.
▶Known glioma risk loci are associated with glioma with a family history of brain tumours—A case–control gene association studyAssociationN=2,972Beatrice Melin et al.(2013)· International Journal of Cancer
A case-control study examining seven known glioma risk loci in individuals with a family history of brain tumours (104 FHBT-glioma cases, 2,868 controls). Three SNPs were associated with glioma risk: rs2736100 (TERT; OR=1.41, 95% CI 1.05-1.89), rs4977756 (CDKN2A-CDKN2B; OR=2.01, p=0.01), and rs6010620 (RTEL1; OR=0.51, p=0.012 for glioblastoma). Only rs6010620 remained significant after correction for multiple comparisons.
▶TERT's role in colorectal carcinogenesisAssociationN=6,225Andrew J. Pellatt et al.(2013)· Molecular Carcinogenesis
Case-control study of 1,555 colon cancer cases and 1,956 controls, plus 754 rectal cancer cases and 959 controls, examining seven TERT SNPs. TERT rs2736118 was associated with increased colon cancer risk (OR=1.31, 95% CI 1.02-1.69), while TERT-CLPTM1L rs2853668 was inversely associated with both colon (OR=0.71, 95% CI 0.55-0.92) and rectal cancer (OR=0.62, 95% CI 0.43-0.90). Three TERT SNPs (rs10069690, rs2242652, rs4246742) showed significant interactions with BMI to influence colon cancer risk, and rs2853668 interacted with aspirin/NSAID use.
▶hTERT Cancer Risk Genotypes Are Associated With Telomere LengthAssociationN=280Beatrice S. Melin et al.(2012)· Genetic Epidemiology
A case-control study of 280 COVID-19 patients (143 hospitalized, 137 non-hospitalized) from Brazil investigated the association of TERT gene polymorphisms rs2853669 and rs2736100 with COVID-19 severity. The rs2853669 G allele was associated with aneurysms/strokes (p=0.026), flu-like illness (p=0.021), hormonal changes (p=0.004), and thromboembolism (p=0.029). The rs2736100 C allele showed increased risk of sepsis (p=0.042) and mortality (p=0.048, OR=1.674). This is the first study examining these TERT polymorphisms in Brazilian COVID-19 patients.
▶The 18p11.22 locus is associated with never smoker non-small cell lung cancer susceptibility in Korean populationsAssociationN=2,375Ahn MJ et al.(2012)· Human Genetics
Genome-wide association study identifying the 18p11.22 locus as a novel susceptibility region for never-smoker non-small cell lung cancer (NSCLC) in Korean populations. Two SNPs (rs11080466, OR=0.68, p=1.08×10⁻⁶; rs11663246, OR=0.69, p=2.32×10⁻⁶) in the FAM38B gene intron were replicated across discovery and independent validation cohorts, with the protective alleles underrepresented in cases.
▶Genome-wide association study of glioma and meta-analysisAssociationN=6,811Rajaraman P. et al.(2012)· Human Genetics
Genome-wide association study of glioma in 1,856 cases and 4,955 controls that confirmed seven previously reported susceptibility loci. Strong replication was found for rs2736100 (TERT, OR=0.72), rs4977756 (CDKN2BAS, OR=1.35), and rs6010620 (RTEL1, OR=0.66). Consistent associations were observed for loci at EGFR, CCDC26, and PHLDB1. Meta-analysis of 85 candidate loci in 5,015 cases and 11,601 controls identified no novel genome-wide significant associations, suggesting glioma genetic architecture may involve fewer common variants than other cancers.
▶Telomere length and genetic analyses in population‐based studies of endometrial cancer riskAssociationN=2,359Jennifer Prescott et al.(2010)· Cancer
This nested case-control study examined the association between relative telomere length and genetic variants in telomere maintenance genes (TERT, TNKS2, POT1, TERF1, TERF2) with endometrial cancer risk in 674 cases and 1,685 controls. Relative telomere length was not significantly associated with endometrial cancer risk (OR=1.20, 95% CI=0.73-1.96). However, variants rs2736122 in TERT (OR=1.18, 95% CI=1.01-1.38) and rs12412538 in TNKS2 (OR=1.16, 95% CI=1.00-1.34) showed elevated endometrial cancer risk, though these associations did not reach statistical significance after multiple comparisons correction.
▶New Insights Into Susceptibility to GliomaReviewYanhong Liu et al.(2010)· Archives of Neurology
This review discusses recent genome-wide association studies (GWAS) that identified five susceptibility loci for glioma: TERT rs2736100 (OR=1.27), CCDC26 rs4295627 (OR=1.36), CDKN2A/CDKN2B rs4977756 (OR=1.24), RTEL1 rs6010620 (OR=1.18), and PHLDB1 rs498872 (OR=1.28). The combined effect shows that individuals with 8 or more risk alleles have over 3-fold increased glioma risk compared to those with median alleles (OR=1.31 per allele, p=1.39×10^-74). These common low-risk variants represent the strongest evidence to date for inherited susceptibility to glioma, with shared associations across multiple cancer types.
▶FunctionalFEN1polymorphisms are associated with DNA damage levels and lung cancer riskAssociationN=288Ming Yang et al.(2009)· Human Mutation
This cross-sectional study of 288 coke oven workers examined gene-environment interactions between FEN1 rs174538 polymorphism and polycyclic aromatic hydrocarbon (PAH) exposure, measured by urinary 1-OH-pyrene levels, on DNA damage in EGFR gene exons 19 and 21. The study found significant linear associations between PAH exposure and EGFR exon damage (P trend < 0.001 for both exons), which were modified by FEN1 rs174538 genotype—the associations were significant only in GA+AA carriers (P < 0.001) but not in GG carriers, suggesting genetic susceptibility influences PAH-induced DNA damage.
▶Meta-analysisN=1,513,186Unknown
Mendelian randomization study of 16 genetic variants in 10 telomere-related loci using summary data from 420,081 cancer cases and 1,093,105 controls. Genetically increased telomere length was associated with higher cancer risk (glioma OR 5.27 [3.15-8.81], lung adenocarcinoma 3.19 [2.40-4.22], neuroblastoma 2.98 [1.92-4.62]) but reduced risk for cardiovascular diseases and some immune conditions.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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