Background: The comprehensive analysis of the mutational status of colon cancer (CC) may identify targetable alterations also in early stages. This may open up potential beneficial treatment choices, e.g. immunotherapy in microsatellite instable (MSI) tumors. So far, there is few data regarding the distribution of molecular alterations in CC in a real world setting in Germany. Methods: We analyzed clinical and molecular data from our Colopredict Plus (CPP) registry trial including CC patients (pts.) stage I-III. Samples were tested for MS status by immunohistochemistry and for gene mutations (MT) using a 71 gene panel comprised for CC. Molecular data was correlated with clinicopathologic parameters. Disease free Survival (DFS) was estimated by the Kaplan-Meier method. Results: Data from 2746 pts. was included. Female: 1476/2746 (53,8 %), median age: 72 yrs (range: 22-100 yrs), right sided tumor: 1607/2746 (58,5 %), stage distribution I/II/III/NA: 414 (15,1 %)/1198 (43,6 %)/1076 (39,2 %)/58 (2,1 %). MSI/MSS: 544(19,8%)/2202/ (80,2%). A KRAS mutation was observed in 846/2746 (30,8 %). The most frequent hotspot MT were codon 12 KRAS MT with p.G12D (27%), p.G12V (19%), p.G12A (6%), and p.G12C (6%) followed by codon 13 MT with p.G13D (18%). The subtypes p.G12D, p.G12V, and p.Q61K were significantly more frequent in the right colon. BRAF MT was seen in 560/2746 (20,4%). Observed rare MT were: POLE (76/2746 (2,8 %), PTEN 188/2746 (6,8 %), and EGFR (21/2746; 0,8%). MSI CC were more frequent in the right colon and associated with BRAF MT (346/560; 61,8 %), and also MT in BRCA1 (35/53; 66 %), BRCA2 (119/171; 69,6 %), POLE (45/76 (59,2 %), PTEN 107/188 (56,9 %), and EGFR (18/21, 85,7%). In contrast, TP53 MT (1223/2746 (44,5 %)) were associated with MSS (1090/2746 (49,5 %)). 3 yrs DFS in MSI BRAF WT vs. MSS BRAF MT pts. was 0,75 (0,67 – 0,81 vs 0,52 (0,36 – 0,65) (p =0,11). DFS did not differ in specific KRAS MT variants. Conclusions: We here show a comprehensive analysis of genetic alterations in early CC in a prospective real world cohort. As expected, MSI was correlated with female sex, right sided primary tumor and BRAF MT. Interestingly, we also found a strong correlation of BRCA1 MT, BRCA2 MT, EGFR MT, POLE MT, and PTEN MT with presence of MSI while MSS was associated with TP53 MT. Broad molecular characterization of early CC may help individualize treatment strategies in the future.