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If you are a researcher, genetic counsellor, or clinician, please consider includingyour patient’s with germline BAP1 variants de-identified data in  the BIG consortium. Without your co-operation this work to find new effective ways to prevent, treat and promote awareness will not be possible. Together we can gain a better understanding and achieve true BAP1 analysis to help those affected with by this variant.   Suggested criteria for testing patients1:

  • Two or more confirmed BAP1-TPDS tumors*

OR

* Excluding two basal cell cancers and/or cutaneous melanomas, given their high frequency in the general population

This is particularly relevant for uveal melanoma and/or mesothelioma diagnoses in families due to their relative rarity in the general population.

Consortium’s guidelines regarding germline BAP1 variants:

  • BAP1 should be included in all germline cancer panels for genetic testing (which should include copy number variation assessment) particularly for patients with tumors associated with the BAP1-TPDS. Additionally as many family members as possible should be genotyped to aid segregation analysis, to directly inform surveillance of carriers and assessment of mutation penetrance.
  • Use of ClinGen disease-gene association framework to evaluate tumor spectrum and more consistency in reporting tumor histopathology, in particular, site/histology of mesotheliomas, histology of RCCs and histology of meningiomas 2.
  • IHC and LOH analysis performed on all tumors in all carriers regardless of variant type.
  • Conduct epidemiological studies evaluating BAP1-inactivated melanocytic tumors in the general population and use recommendations proposed by Haugh et al and Cabaret et al 3,4 in the evaluation of these tumors.
  • Although a useful aid, do not use functional assays as a definitive evaluation of pathogenicity of BAP1 variants until proof that function is linked to tumorigenesis in vivo.
  • Pathogenicity of missense variants needs to be evaluated beyond in silico prediction and single functional assays. Currently, family assessment (e.g. segregation of core BAP1-TPDS tumors; core rare tumors (UM/mesothelioma) in the family without segregation data; multiple primary BAP1-TPDS core tumors in the proband, or a combination of these) and tumor analysis are the most important tools.
  • Implementation and expansion of current and appropriate surveillance measures for variant carriers. The current suggested guidelines are published in GeneReviews 1 .

Surveillance of carriers:

As mentioned above, we recommend using the current measures in the guidelines published in GeneReviews. We believe these surveillance measures are essential for appropriate management of carriers.

1-Pilarski, R., Rai, K., Cebulla, C. & Abdel-Rahman, M. in GeneReviews((R))   (eds M. P. Adam et al.)  (University of Washington, Seattle, 2016).

2-Strande, N. T. et al. Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource. American journal of human genetics 100, 895-906, doi:10.1016/j.ajhg.2017.04.015 (2017).

3-Cabaret, O., Perron, E., Bressac-de Paillerets, B., Soufir, N. & de la Fouchardiere, A. Occurrence of BAP1 germline mutations in cutaneous melanocytic tumors with loss of BAP1-expression: a pilot study. Genes, chromosomes & cancer, doi:10.1002/gcc.22473 (2017).

4-Haugh, A. M. et al. Genotypic and Phenotypic Features of BAP1 Cancer Syndrome: A Report of 8 New Families and Review of Cases in the Literature. JAMA dermatology, doi:10.1001/jamadermatol.2017.2330 (2017).