Pathogenic germline variants in patients with features of hereditary renal cell carcinoma: Evidence for further locus heterogeneity

Philip S Smith, Hannah West, James Whitworth, Bruce Castle, Francis H Sansbury, Anne Y Warren, Emma R Woodward, Marc Tischkowitz, Eamonn R Maher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Inherited renal cell carcinoma (RCC) is associated with multiple familial cancer syndromes but most individuals with features of non-syndromic inherited RCC do not harbor variants in the most commonly tested renal cancer predisposition genes (CPGs). We investigated whether undiagnosed cases might harbor mutations in CPGs that are not routinely tested for by testing 118 individuals with features suggestive of inherited RCC (family history of RCC, two or more primary RCC aged <60 years, or early onset RCC ≤46 years) for the presence of pathogenic variants in a large panel of CPGs. All individuals had been prescreened for pathogenic variants in the major RCC genes. We detected pathogenic or likely pathogenic (P/LP) variants of potential clinical relevance in 16.1% (19/118) of individuals, including P/LP variants in BRIP1 (n = 4), CHEK2 (n = 3), MITF (n = 1), and BRCA1 (n = 1). Though the power to detect rare variants was limited by sample size the frequency of truncating variants in BRIP1, 4/118, was significantly higher than in controls (P = 5.92E-03). These findings suggest that the application of genetic testing for larger inherited cancer gene panels in patients with indicators of a potential inherited RCC can increase the diagnostic yield for P/LP variants. However, the clinical utility of such a diagnostic strategy requires validation and further evaluation and in particular, confirmation of rarer RCC genotype-phenotype associations is required.

Original languageEnglish
Pages (from-to)5-16
Number of pages12
JournalGenes, chromosomes & cancer
Issue number1
Early online date23 Aug 2020
Publication statusPublished - Jan 2021


  • Adolescent
  • Adult
  • Aged
  • BRCA1 Protein/genetics
  • Carcinoma, Renal Cell/genetics
  • Checkpoint Kinase 2/genetics
  • Child
  • Fanconi Anemia Complementation Group Proteins/genetics
  • Female
  • Genetic Heterogeneity
  • Genetic Testing/methods
  • Germ-Line Mutation
  • Humans
  • Kidney Neoplasms/genetics
  • Male
  • Microphthalmia-Associated Transcription Factor/genetics
  • Middle Aged
  • RNA Helicases/genetics


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