Pathogenic MUYTH and Novel H3F3A Variants in Glioblastoma: A Case Report and Literature Review (P4-5.005).

Objective: We describe a novel somatic variant in the histone gene in a glioblastoma patient with monoallelic pathogenic variant. We computationally characterize this histone variant and review the literature for histone variants in patients with variants and glioblastoma.

Background: Glioblastoma has a demonstrated association with inherited polyposis syndromes, including those due to biallelic pathogenic variants in . Moreover, there is an emerging understanding of the germline genetic background on which glioblastoma arises. For instance, somatic histone variants in glioblastoma have been hypothesized to co-occur in those with monoallelic germline variants in , but few cases have been reported.

Design/methods: We report a case of a patient with glioblastoma and a presumed monoallelic germline pathogenic variant in , found on tumor genomic profiling to have a somatic variant of uncertain significance (VUS). We characterized this variant using Variant Effects Predictor, PolyPhen-2, and SIFT, and reviewed literature relating to somatic histone variants in glioblastoma.

Results: A 66-year-old right-handed female presented with one year of right hemibody weakness, hypoesthesia, incoordination, and expressive aphasia. A left frontal mass was biopsied and found to be a glioblastoma, WHO Grade 4, IDH-wildtype, MGMT hypermethylated. Tumor genomic profiling revealed a pathogenic variant in (p.Y179C, variant allele frequency 49%) and a VUS in (p.R3C, variant allele frequency 23%). Her variant in had not been previously characterized in glioblastoma. Mixed effects are predicted by computational tools: neutral impact with 65% certainty (PredictSNP2), likely pathogenic (FATHMM-XF), possibly damaging (Variant Effects Predictor, PolyPhen-2), and deleterious (low confidence, SIFT). Literature review identified a report of a neighboring variant, p.R2C, also predicted to associate with glioma.

Conclusions: Our report augments the hypothesized association between monoallelic germline pathogenic variants in and histone variant glioblastoma, reporting a novel somatic variant with putative deleterious effects. Mr. Rilinger has nothing to disclose. Dr. Dhawan has nothing to disclose.