Mutated versions or overexpression of receptor tyrosine kinases such as the epidermal growth factor receptor are found frequently in various cancers. In Xiphophorus the formation of hereditary melanoma is caused by the overexpression of the Xmrk oncogene locus. Xmrk is a mutationally altered version of the epidermal growth factor receptor. Two amino acid changes in the extracellular domain of the receptor were shown in vitro to be responsible for a constitutive, ligand-independent activity of Xmrk. To analyze whether these two mutations are indeed responsible for the in vivo oncogenic activity of the receptor, both were independently introduced into the wild-type, non-oncogenic Xiphophorus EGF-receptor and tested in Medaka embryos for their tumorigenic capacity. Both mutations were sufficient to induce tumors after short latency periods and at a comparable frequency as the native Xmrk oncogene. The G359R mutation led to a significantly higher tumor rate than the C578S mutation. Our study shows that subtle point mutations of the EGF-receptor can lead to a highly tumorigenic oncoprotein.