39. Modifying cancer variant interpretation guidelines for the curation of histone H3 variants: The 'next step' of the Cl

Histone H3 variants pose numerous challenges for curation due to varied nomenclature for their isoforms and encoding genes. These are further compounded by the tumor-specific settings in which histone H3 variants occur. Therefore, the Histone H3 SC-VCEP aimed to adapt and modify the ClinGen/CGC/VICC Oncogenicity SOP and AMP/ASCO/CAP guidelines for the interpretation of H3 variants specific to diffuse midline glioma, H3 K27-altered and diffuse hemispheric glioma, H3 G34-mutant.

The main proposed specifications to the ClinGen/CGC/VICC Oncogenicity SOP include: (1) the incorporation of trimethylation loss at the K27 residue and functional studies at G34 into evidence code OS2 and (2) stipulation of location at a 'conserved residue affecting epigenetic modification (e.g. histone H3 K27, G34, or K36)' for evidence code OM1.

The main proposed modifications to the ClinGen/CGC/VICC Oncogenicity SOP include: (1) an 'OS1_moderate' criterion (2 points), allowing for the same amino acid change as a previously established oncogenic variant in a homologous H3 gene; (2) an 'OS2_supportive' criterion (1 point), incorporating supportive evidence of frequent co-occurring variants (e.g. TP53, PDGFRA, ACVR1) or other supportive evidence of histone H3 mutation (e.g. gene expression analysis); and (3) an alternate OP2 criterion (1 point) applied when clinicopathologic features align with a corresponding histone mutant glioma in the WHO Classification. This novel modification introduces clinicopathological correlation into the assessment of oncogenicity. Evidence specifications have also been made to the AMP/ASCO/CAP guidelines.

Evaluation of our proposed changes to the guidelines is underway in a defined set of pilot variants.