Functional characterisation guides classification of novel BAP1 germline variants

Jing Han Hong,Jing Tan,Hong Lee Heng,Nur Diana Binte Ishak,Bin Tean Teh,Po-Hsien Lee,Joanne Ngeow,Siao Ting Chong,Sock Hoai Chan

doi:10.1038/s41525-020-00157-6

Abstract

We have identified six patients harbouring distinct germline BAP1 mutations. In this study, we functionally characterise known BAP1 pathogenic and likely benign germline variants out of these six patients to aid in the evaluation and classification of unknown BAP1 germline variants. We found that pathogenic germline variants tend to encode truncated proteins, show diminished expression of epithelial-mesenchymal transition (EMT) markers, are localised in the cytosol and have reduced deubiquitinase capabilities. We show that these functional assays are useful for BAP1 variant curation and may be added in the American College of Medical Genetics and Genomics (ACMG) criteria for BAP1 variant classification. This will allow clinicians to distinguish between BAP1 pathogenic and likely benign variants reliably and may aid to quickly benchmark newly identified BAP1 germline variants. Classification of novel BAP1 germline variants allows clinicians to inform predisposed patients and relevant family members regarding potential cancer risks, with appropriate clinical interventions implemented if required.

Highlights

BAP1 (BRCA1-associated protein) is a nuclear localised deubiquitinating enzyme that is made up of a ubiquitin carboxyl hydrolase (UCH) domain, a host cell factor 1 (HCF1) binding domain, a Cterminal domain with a coiled-coil motif and a nuclear localisation signal[1,2,3]
Clinicopathological characteristics of patients with germline BAP1 variants Through clinical genetic testing, we identified six patients harbouring germline BAP1 mutations (Table 1, Supplementary Data 1)
BAP1 tumour predisposition syndrome is a hereditary tumour syndrome that is associated with germline pathogenic mutations in BAP121 and increased susceptibility for uveal melanoma, mesothelioma, cutaneous melanoma and renal cell carcinoma[42]

Summary

Introduction

BAP1 (BRCA1-associated protein) is a nuclear localised deubiquitinating enzyme that is made up of a ubiquitin carboxyl hydrolase (UCH) domain, a host cell factor 1 (HCF1) binding domain, a Cterminal domain with a coiled-coil motif and a nuclear localisation signal[1,2,3]. BAP1 germline variants predispose individuals to high risks of development of aggressive cancers, such as, uveal melanoma, mesothelioma, cutaneous melanoma and renal cell carcinoma at a younger age with poor prognosis[15]. As of April 2020, 466 BAP1 germline variants of uncertain significance (VUS) have been reported on ClinVar, with 447 of them having single nucleotide variations and 404 of them resulting in missense mutations[22]. More of such BAP1 variants are expected to be discovered as clinical laboratories have increasingly adopted next-generation sequencing to diagnose hereditary disorders due to its costeffectiveness, high throughput and accuracy[23]. Classification of VUS allows us to inform predisposed patients and affected family members regarding potential cancer risks, with appropriate clinical interventions implemented if necessary

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Conclusion