Germline BAP1 mutations predispose to renal cell carcinomas

Am J Hum Genet. 2013 Jun 6;92(6):974-80. doi: 10.1016/j.ajhg.2013.04.012. Epub 2013 May 16.


The genetic cause of some familial nonsyndromic renal cell carcinomas (RCC) defined by at least two affected first-degree relatives is unknown. By combining whole-exome sequencing and tumor profiling in a family prone to cases of RCC, we identified a germline BAP1 mutation c.277A>G (p.Thr93Ala) as the probable genetic basis of RCC predisposition. This mutation segregated with all four RCC-affected relatives. Furthermore, BAP1 was found to be inactivated in RCC-affected individuals from this family. No BAP1 mutations were identified in 32 familial cases presenting with only RCC. We then screened for germline BAP1 deleterious mutations in familial aggregations of cancers within the spectrum of the recently described BAP1-associated tumor predisposition syndrome, including uveal melanoma, malignant pleural mesothelioma, and cutaneous melanoma. Among the 11 families that included individuals identified as carrying germline deleterious BAP1 mutations, 6 families presented with 9 RCC-affected individuals, demonstrating a significantly increased risk for RCC. This strongly argues that RCC belongs to the BAP1 syndrome and that BAP1 is a RCC-predisposition gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Base Sequence
  • Carcinoma, Renal Cell / enzymology
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / pathology
  • Exome
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • Humans
  • Kidney Neoplasms / enzymology
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA
  • Tumor Suppressor Proteins / genetics*
  • Ubiquitin Thiolesterase / genetics*


  • BAP1 protein, human
  • Tumor Suppressor Proteins
  • Ubiquitin Thiolesterase