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Background: Colorectal cancer (CRC) is among all common malignancies one with the highest percentage of familial clustering. Thus almost 20% of cases develop in families with at least another affected member. Individuals in these families have a higher risk of developing CRC. Known mutations responsible for several CRC syndromes only explain a small proportion of familial cases but the underlying basis of most still remains unknown. Over half of CRCs that are highly suspicious for an autosomal dominant hereditary pattern of malignancy, as expressed by the Amsterdam criteria, are not explained by known genetic mutations. These cases are known as microsatellite stable hereditary non-polyposis CRC (MSS-HNPCC) or colorectal cancer type X. Aims: To identify new genetic variants that can potentially modulate CRC risk and contribute to hereditability. Methods: We sequenced the coding sequence of MGMT, AXIN2, CTNNB1, TGFβRI and TGFβRII genes and we genotyped 10 common low risk variants, in 30 MSS-HNPCC patients. Potentially relevant variants were genotyped in 308 sporadic cases and 425 cancer-free controls. Logistic regression was used to estimate cancer risk (OR (95%CI)) associated with the genetic variants identified using SPSS (IBM v20.0). Results: A haplotype containing 3 variants (rs67687202, rs868 and rs334354) in high linkage disequilibrium (LD) was found to be associated in a very strong manner with MSS-HNPCC patients and to a lesser degree with sporadic CRC. Thus both MSS-HNPCC and sporadic CRC showed a significantly lower minor allele frequency (MAF) than controls (MAF 0.07, MAF 0.23 vs MAF 0.29) for rs67687202. The AA genotype of rs868 associates with a strong risk for CRC in MSS-HNPCC patients (OR=7.9 (2.7-23.1) P Citation Format: Rosa M. Munoz Xicola, Brian Doyle, Jamie Rawson, Pilar Garre, Anna Abuli, Esther Lee, Sathyaraj Murugappan, Xavier Bessa, Luis Bujanda, Francesc Balaguer, Sergi Castellvi-Bel, Juan Clofent, Cristina Alenda, Rodrigo Jover, Clara Ruiz-Ponte, Sapna Singal, Montserrat Andreu, Angel Carracedo, Antoni Castells, Nathan Ellis, Trinidad Caldes, Xavier LLor. Implication of the 3′UTR region of TGFβR1 with MSS HNPCC and sporadic colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1334. doi:10.1158/1538-7445.AM2013-1334