A patient with a SETD2 LOF variant developed multiple brain stem gliomas (SETD2-LLS-P2) from age 6 years and a patient (SETD2-R1740W-P4) with Type 1 (R1740W) variant with a metastatic high-grade chondroblastic osteosarcoma in her right proximal tibia and right mandible age 15 years. Here, SETD2 is linked to brain stem glioma.