KMT2C encodes a histone H3 lysine 4 (H3K4) methyltransferase that catalyzes monomethylation at chr7 sites where transcription and DNA repair occur 1. The protein forms part of chr7 remodeling machinery and works redundantly with KMT2D to enrich H3K4me1 marks on primed and active enhancer elements 2. KMT2C functions as a tumor suppressor, with loss-of-function mutations occurring frequently in breast cancer (10-20%) and other malignancies 3. In prostate cancer, KMT2C deficiency promotes transdifferentiation to double-negative prostate cancer following androgen deprivation therapy by maintaining enhancer activity at AR-regulated genes 4. Pathogenic variants in KMT2C cause Kleefstra syndrome 2, a neurodevelopmental disorder characterized by developmental delay, intellectual disability, behavioral problems, hypotonia, seizures, and short stature 5. Notably, approximately 15% of protein-truncating variants are inherited from asymptomatic parents, indicating incomplete penetrance 56. The clinical phenotype is distinct from other histone methyltransferase disorders like Kabuki syndrome, with unique facial features and DNA methylation signatures 5. KMT2C represents a critical epigenetic regulator whose dysfunction contributes to both cancer development and neurodevelopmental disorders.