ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
21874000 Testa et al 2011 identified two families with high incidence of mesothelioma and sequenced for causal germline variants. Two germline truncating variants (nonsense and splice) were identified. Family L 9 segregations of BAP1 Exon 16 (52,436,624 C>T, nonsense) with various implicated cancers including mesothelioma, uveal melanoma, pancreatic cancer and skin cancer. Family W has 7 segregations of BAP1 Intron 6 (52,441,334 A>G-splice site) with cancers of mesothelioma, breast, renal and ovarian. 7 cancer samples for these families were tested as well, and 4 of the 7 revealed second hits in BAP1, with loss of heterozygosity in regions encompassing BAP1 or no expression of BAP1. 3 tumor samples were not determined. This emphasizes the likely two-hit nature of BAP1, in that a single inherited germline mutations in BAP1 would not alone be causal in cancer, but combined with a loss or mutation event of the second allele would cause a cancer phenotype.
21941004 Abdel-Rahman 2013 identified a BAP1 nonsense mutation Q267X in a family with 6 segregations and cancers of uveal melanoma, mesothelioma, meningioma and lung adenocarcinoma. In three family members, tumor samples were available and all had loss of heterogyzosity including BAP1. This indicates that the tumor phenotype is expressed upon bi-allelic inactivation of BAP1.
21874003 Weisner et al reports on two families with melanocytic tumors displaying BAP1 mutations. In family 1 three segregations of a frameshift mutation in BAP1 (c.1305delG, p.Gln436Asnfs*135) were identified. BAP1 presence was queried in 29 skin tumors and uveal melanoma samples, and all displayed loss of wildtype BAP1. Family 2 carried a splice mutation that removed the acceptor splice site at the last exon (c.2057-2A>G, p.Met687Glufs*28), which was confirmed by cDNA as a splicing mutation that failed to remove the last intron of BAP1. This pedigree displays 5 segregations. In 9/13 tumors, wildtype BAP1 was lost.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.