Purpose The RET protooncogene plays a crucial role in neural crest development; accordingly, mutations of RET cause MEN2A and familial medullary thyroid carcinoma, while the expression deregulation of RET is involved in the pathophysiology of glioblastoma multiforme (GBM) and pancreatic cancer (PDAC). The aim of this study was to evaluate if germline variants of the RET protooncogene are associated with GBM, pancreatic cancer and gastric cancer (GC). Methods Genomic DNA from peripheral blood was isolated from 100 patients with GBM, 65 patients with GC and 54 patients with PDAC. The coding sequence of RET promoter, exon 2 and exon 13 was amplified. Sequence variations at ?5 and ?1 in the promotor and in exon 2 were determined through a LightCycler assay, and analysis of exon 13 was carried out by genomic sequencing. Results There was no significant association of the RETpromoter or exon 2 genotypes with the phenotype in the different populations, although there was an increase of the GG genotype of the ?5G>A variant in all cancers compared to controls. Sequencing of exon 13 identified mutation c.2372A>T in codon 791 (Y791F) in heterozygous state in one of 100 GBM patients, in two of 65 patients with gastric cancer, in two of 54 PDAC patients and in none of the controls. Conclusions Although our data did not reach significance in our small cohorts, we cannot rule out the involvement of the ?5G promoter allele and the c.2372A>T mutation in the development of the aforementioned tumours.