TFG-Containing Fusions in Melanocytic Tumors: From Polymorphic Read-Through Transcripts to Oncogenic Kinase Fusions

Molecular analysis has emerged as an important ancillary method for the diagnosis and treatment of melanocytic tumors. Test results are often helpful but can occasionally be confounding if an unfamiliar variant is identified. We report a series of melanocytic tumors, which were found to harbor a TFG gene fusion and their significance. Of 105 melanocytic tumors with gene fusions, 9 involved TGF (8.6%). One tumor harbored a TFG::NTRK3 fusion, more precisely characterized as an NTRK3 fusion with TFG as the 5' partner, the detection of which was diagnostically helpful by indicating the presence of a Spitz pathway. Eight cases exhibited a TFG::ADGRG7 fusion. Current evidence suggests that this recurrent event represents a polymorphic germline variant, possibly arising from read-through transcription (intergenic splicing), rather than a biologically pathogenic driver. It should be noted that laboratory reporting practices vary, and not all laboratories report such transcripts in official molecular pathology reports. Recognition of such fusions is essential to avoid misinterpretation, particularly as fusion detection increasingly informs diagnosis and clinical decision-making. These findings underscore the necessity of integrating molecular results with established clinicopathologic frameworks.