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Objective A 6 bp deletion polymorphism in the thymidylate synthase (TS) gene was investigated in order to determine its function.Methods A luciferase system was used to investigate the function of the 6 bp/1494 polymorphism in vitro. A group of 43 patients with colorectal carcinoma were evaluated for the 6 bp/1494 polymorphism and for intratumoral TS mRNA levels in vivo.Results The 3′UTR of TS containing the +6 bp polymorphism resulted in a ∼35% decrease in luciferase activity and mRNA levels, while the TS-3′UTR bearing the −6 bp deletion resulted in a ∼70% decrease in luciferase activity and mRNA levels. The TS-3′UTR construct containing the −6 bp/1494 deletion also had a higher rate of message degradation compared to the +6 bp/1494 construct. Individuals homozygous for the insertion (+6 bp/+6 bp) had significantly higher TS mRNA levels compared to individuals that were homozygous for the deletion (−6 bp/−6 bp) (P< 0.007). We determined the frequency of the −6 bp/1494 deletion polymorphism to be 41% in non-Hispanic whites, 26% in Hispanic whites, 52% in African-Americans and 76% in Singapore Chinese.Conclusions These results suggest that the −6 bp/1494 deletion polymorphism in the 3′UTR of TS is associated with decreased mRNA stability in vitro and lower intratumoral TS expression in vivo. Further, the 6 bp/1494 polymorphism varies greatly within different ethnic populations and is in linkage disequilibrium with the TS 5′ tandem repeat enhancer polymorphism. Taken together, these data suggest that the 6 bp/1494 polymorphism may be a useful screening tool in predicting TS mRNA expression.