103. Formation of a ClinGen Variant Curation Expert Panel (VCEP) dedicated to Oncohistone H3 Variants in Pediatric Gliomas

Aly Abdelkareem

David Meredith

David Meredith, MD, PhD, is a neuropathologist at Brigham and Women’s Hospital. He received his MD/PhD dual degree from the University of Texas Southwestern Medical Center at Dallas and completed anatomic pathology and neuropathology training at Brigham and Women’s Hospital and Harvard Medical School. His clinical responsibilities include neuropathology, soft tissue pathology, and molecular diagnostics with specialization in the interpretation of next generation sequencing results in brain tumors.


David Mereditha, Jason Salibab, Yassmine Akkaric, Wan-Hsin Lind, Jianling Jie, Elizabeth Spiterif, Cam Grisdaleg, Arpad Danosb, Rushil Duah, Erin McMullini, Jeanine Ruggerij, Eldar Dudick, Donald Parsonsl, Daniel Bratm, Sebastian Waszakn, Sabine Muellern, Obi L. Griffithb, Malachi Griffithb, Laveniya Satgunaseelano

aBrigham and Women’s Hospital, Boston, MA, USA; bWashington University, St. Louis, MO, USA; cLegacy Health, Portland, OR, USA; dMayo Clinic, Rochester, MN, USA; eChildren’s Hospital Los Angeles, Los Angeles, CA, USA; fStanford Medicine, Palo Alto, CA, USA; gBC Cancer, Vancouver, BC, CA; hUniversity of Ottawa, Ottawa, ON, CA; iBard College at Simon’s Rock, Great Barrington, MA, USA; jUniversity of Michigan, Ann Arbor, MI, USA; kIndependent Contractor, Tuzla, Bosnia and Herzegovina; lBaylor College of Medicine, Houston, TX, USA; mNorthwestern University, Chicago, IL, USA; nUniversity of California San Francisco, San Francisco, CA, USA; oRoyal Prince Alfred Hospital, Sydney, NSW, Australia

Mutations in histone H3 (oncohistones) result in widespread epigenetic dysregulation and are increasingly recognized as oncogenic events in many different cancer types. In particular, H3.1/3 K27M and G34R/V oncohistones define a subset of highly aggressive pediatric gliomas arising in the midline (‘diffuse midline glioma, H3 K27-altered’) and cerebral hemispheres (‘diffuse hemispheric glioma, H3 G34-mutant’). Recently, other glioma subtypes with non-infiltrative or low-grade histomorphologies have been identified with H3 K27M mutations and less aggressive clinical courses, some harboring co-occurring driver events characteristic of low-grade gliomas, such as BRAF V600E. Such tumors are not currently classified as ‘diffuse midline glioma, H3 K27-altered’, emphasizing the need to consider oncohistones within a broader clinicopathologic context.

We have thus formed a variant curation expert panel (SC-VCEP) composed of both clinical and scientific experts to develop a sustainable workflow for systematic consensus review of oncogenic alterations in H3 encoding genes that drive tumor development and response to targeted therapy. Our group will apply AMP/ASCO/CAP guidelines and the ClinGen/CGC/VICC Oncogenicity SOP to curate somatic single nucleotide variants in H3 encoding genes (e.g., H3-3A) and harmonize the diverse nomenclature at the gene, protein, and variant level. After consensus classification, the panel will document supporting evidence and make these interpretations publicly available through CIViC and ClinVar knowledgebases. The workflow will also integrate clinicopathological information (age of onset, location, histology) and co-occurring mutations in the curation effort, given their necessity for accurate diagnosis and prognostication of histone-mutant gliomas.