Abstract Details

Title Pathogenic MUYTH and Novel H3F3A Variants in Glioblastoma: A Case Report and Literature Review

Topic Neuro-oncology

Presentation(s) P4 - Poster Session 4 (11:45 AM-12:45 PM)

Poster/Presentation
Number 5-005

Objective We describe a novel somatic variant in the histone H3F3A gene in a glioblastoma patient with monoallelic MUTYH pathogenic variant. We computationally characterize this histone variant and review the literature for histone variants in patients with MUTYH variants and glioblastoma.

Background Glioblastoma has a demonstrated association with inherited polyposis syndromes, including those due to biallelic pathogenic variants in MUTYH. 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 MUTYH, 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 MUYTH, found on tumor genomic profiling to have a somatic H3F3A 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 MUYTH (p.Y179C, variant allele frequency 49%) and a VUS in H3F3A (p.R3C, variant allele frequency 23%). Her variant in H3F3A 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, H3F3A p.R2C, also predicted to associate with glioma.

Conclusions Our report augments the hypothesized association between monoallelic germline pathogenic variants in MUTYH and histone variant glioblastoma, reporting a novel somatic H3F3A variant with putative deleterious effects.

Authors/Disclosures
Ryan Rilinger PRESENTER	Mr. Rilinger has nothing to disclose.
Christine Cordova	No disclosure on file
Andrew Dhawan, MD (Cleveland Clinic)	Dr. Dhawan has nothing to disclose.

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