PTCH2 encodes a transmembrane receptor that functions as a negative regulator of the Hedgehog signaling pathway 1. As a patched homologue, PTCH2 acts as a receptor for Sonic hedgehog ligand and suppresses the pathway by inhibiting the Smoothened receptor 1. This signaling cascade ultimately controls cellular growth and proliferation through regulation of GLI transcription factors 2. PTCH2 is upregulated in basal cell carcinomas and medulloblastomas, suggesting dysregulation contributes to malignant transformation 34. Aberrant activation of Hedgehog signaling through PTCH2 mutations or alterations drives these cancers primarily through ligand-independent mechanisms 1. Pathogenic PTCH2 variants have been identified in childhood cancer survivors with central nervous system cancers 5, and rare deleterious variants of PTCH2 may predispose carriers to reproductive cancers 6. However, PTCH2 should not be considered a major Gorlin syndrome gene, as high frequencies of loss-of-function variants exist in the general population without associated phenotypes 7. Hedgehog pathway inhibitors targeting downstream SMO represent therapeutic strategies for PTCH2-associated malignancies 8.