Functional characterisation guides classification of novel BAP1 germline variants

Area of Science:

• Genetics
• Molecular Biology
• Oncology

Background:

• Germline mutations in the BAP1 gene are associated with increased cancer predisposition.
• Accurate classification of BAP1 variants is crucial for clinical management and genetic counseling.
• Distinguishing pathogenic from benign BAP1 variants remains a challenge.

Purpose of the Study:

• To functionally characterize known BAP1 germline variants from six patients.
• To establish functional assays for evaluating and classifying novel BAP1 germline variants.
• To propose the integration of functional assays into the American College of Medical Genetics and Genomics (ACMG) variant classification criteria.

Main Methods:

• Analysis of distinct germline BAP1 mutations in six patients.
• Functional characterization of known BAP1 pathogenic and likely benign variants.
• Assessment of protein truncation, epithelial-mesenchymal transition (EMT) marker expression, subcellular localization, and deubiquitinase activity.

Main Results:

• Pathogenic BAP1 germline variants were associated with truncated proteins.
• Diminished expression of EMT markers was observed with pathogenic variants.
• Pathogenic variants showed altered subcellular localization (cytosolic) and reduced deubiquitinase capabilities.
• Functional assays demonstrated utility in BAP1 variant curation.

Conclusions:

• Functional assays provide reliable methods for BAP1 variant classification.
• These assays can aid in distinguishing pathogenic from likely benign BAP1 variants.
• Improved BAP1 variant classification can inform patients about cancer risks and guide clinical interventions.