Classification of variants is pivotal to determine level of interventions required for appropriate care and surveillance of individuals. The American College of Medical Genetics(AMCG) has guidelines for the interpretation of variants generally available online 1. All variants that are presumed to cause null variants (nonsense, frameshift deletions and insertions resulting in early termination, variants in canonical splice sites and larger deletions) meaning they result in a truncated protein should be treated as pathogenic. The ACMG does not classify canonical splice site variants as pathogenic, only likely pathogenic, unless evidence of disrupted protein. This can easily be tested but it is safe to assume that canonical splice variants in BAP1 are pathogenic.
The more difficult problem surrounding BAP1 is the large number of variants of unknown significance (VUS) found in families including missense and intronic variants. It is generally thought most of these variants in tumour suppressors are benign. However, there are reported missense variants resulting in splicing and disrupted protein as well as other missense variants that have the BAP1-TPDS phenotype with unproven splicing 2,3. When presented with a VUS in BAP1, clinicians/genetic counsellors should follow the ACMG guidelines, but it is imperative that phenotypical evidence is the defining factor in the classification. If public database sources classify a variant as benign but a family presents with a distinct phenotype, the RNA should be tested for BAP1 levels as well as tumours examined for functional evidence linking BAP1 to tumourigenesis.
1-Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine : official journal of the American College of Medical Genetics 17, 405-424, doi:10.1038/gim.2015.30 (2015).
2-Popova, T. et al. Germline BAP1 mutations predispose to renal cell carcinomas. American journal of human genetics 92, 974-980, doi:10.1016/j.ajhg.2013.04.012 (2013).
3-Wadt, K. et al. A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma. Pigment cell & melanoma research 25, 815-818, doi:10.1111/pcmr.12006 (2012).