Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases

Bryndis Yngvadottir, Avgi Andreou, Laia Bassaganyas, Alexey Larionov, Alex J. Cornish, Daniel Chubb, Charlie N. Saunders, Philip S. Smith, Huairen Zhang, Yasemin Cole, James Larkin, Lisa Browning, Samra Turajlic, Kevin Litchfield, Richard S. Houlston, Eamonn R. Maher

Research output: Contribution to journalArticlepeer-review


Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes, but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic and likely pathogenic (P/LP) germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. Whole-genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100 000 Genomes Project, a nationwide multicentre study, was analyzed to identify rare P/LP short variants (single nucleotide variants and insertions/deletions ranging from 1 to 50 base pairs) and structural variants in 121 CSGs. Among 1336 RCC participants [mean: 61.3 years (±12 SD), range: 13-88 years; 64% male], 85 participants [6.4%; 95% CI (5.1, 7.8)] had one or more P/LP germline variant in a wider range of CSGs than previously recognized. A further 64 intragenic variants in CSGs previously associated with RCC were classified as a variant of uncertain significance (VUS) (24 'hot VUSs') and were considered to be of potential clinical relevance as further evaluation might results in their reclassification. Most patients with P variants in well-established CSGs known to predispose to renal cell carcinoma (RCC-CSGs) were aged <50 years. Burden test analysis for filtered variants in CSGs demonstrated a significant excess of CHEK2 variants in European RCC participants compared with the healthy European controls (P = 0.0019). Approximately, 6% of the patients with RCC unselected for family history have a germline variant requiring additional follow-up analysis. To improve diagnostic yield, we suggest expanding the panel of RCC-CSGs tested to include CHEK2 and all SDHx subunits and raising the eligibility criteria for age-based testing.

Original languageEnglish
Pages (from-to)3001-3011
Number of pages11
JournalHuman Molecular Genetics
Issue number17
Early online date20 Apr 2022
Publication statusPublished - 1 Sept 2022

Bibliographical note

Copyright © The Author(s) 2022. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.


  • cancer
  • renal cell carcinoma
  • genes
  • genome
  • diagnosis
  • neoplasms
  • chek2 gene
  • whole genome sequencing


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