Clinical Domain Working Groups

The H3 expert panel will develop a sustainable workflow for systematic consensus review of oncogenic alterations in H3-3A (H3F3A), H3C1 (HIST1H3A), H3C2 (HIST1H3B), and other histone H3 encoding genes that drive tumor and response to targeted therapy. As the nomenclature of histone H3 varies greatly within the literature (Table 1 & 2), we will focus on harmonization at the gene variant level. Somatic single nucleotide variants (SNVs) in H3 encoding genes related to their diagnostic, prognostic and therapeutic significance will be curated. The group will concentrate on further specifying the AMP/ASCO/CAP guidelines (PMID: 27993330) and piloting the ClinGen/CGC/VICC Oncogenicity SOP for somatic variant classification on H3 alterations. After consensus classification, the panel will make these interpretations publicly available through CIViC and ClinVar knowledgebases.

The workflow will also integrate clinicopathological information (age of onset, location, pattern of infiltration) in the curation of H3 variants, as it is crucial for the accurate diagnosis and prognostication of histone-mutant gliomas. Two histone-mutant gliomas subtypes have been defined in the latest WHO Classification of Tumours of the Central Nervous System (5th edition, 2021) based on their location and amino acid alteration (‘diffuse midline glioma, H3 K27-altered’ and ‘diffuse hemispheric glioma, H3 G34-mutant’). Both entities unfortunately have a dismal prognosis and are designated as CNS WHO Grade 4. Recently however, other glioma subtypes with non-infiltrative or low grade histomorphologies have also been found to harbor H3 K27 mutations, without exhibiting the same aggressive clinical course. Current clinical practice recommendations suggest avoiding classifying such tumors as “diffuse midline glioma, H3 K27-altered”; however, further investigation is required to determine if such entities warrant separate classification. Thus, the H3 expert panel workflow will reflect the need to integrate clinical information for precise curation and classification of all gliomas harboring H3 variants.

While the above efforts will be initially conducted for glial tumors, this SC-VCEP will subsequently expand the scope of its guideline specifications to the annotation of additional Histone H3 SNVs (e.g., H3 K36M and H3 G34W) involved in other mesenchymal and epithelial tumor types. The aim would be to apply the newly created and approved rules to generate expert-panel approved variant submissions.