Activating germline mutations in the fibroblast growth factor receptor (FGFR) gene family have been identified in several dominantly inherited skeletal disorders; in the case of FGFR3, the same somatically arising mutations have also been isolated from a variety of tumour tissues. Whilst the role of FGFR2 mutations in congenital syndromes has been well documented, their relationship with cancer has not been clearly defined. Based on evidence that gain-of-function mutations in FGFR2 drive positive selection in adult spermatogonia, the present study investigated, by denaturing high-performance liquid chromatography (DHPLC), DNA sequencing, and restriction digestion, the prevalence of FGFR2 mutations in 58 tumour cell lines of various types, and 29 testicular germ cell tumour samples. Although sequence variations and allelic imbalance were identified in FGFR2, none of the previously documented dominant mutations was detected in any of the tumour types examined. This suggests that gain-of-function FGFR2 mutations are not commonly encountered in tumourigenesis and specifically excludes a major contribution in testicular tumours. Copyright (c) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.