{"doi":"10.1093/hmg/ddac089","title":"Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases","abstract":"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.","journal":"Human Molecular Genetics","year":2022,"id":246794,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":36,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8722,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":883536,"name":"Avgi Andreou","orcid":"0000-0001-5389-718X","position":1,"is_corresponding":false},{"id":237922,"name":"Laia Bassaganyas","orcid":"0000-0002-4575-0214","position":2,"is_corresponding":false},{"id":883537,"name":"Alexey A. Larionov","orcid":"0000-0001-6374-9391","position":3,"is_corresponding":false},{"id":883538,"name":"Alex J. Cornish","orcid":"0000-0002-3966-3501","position":4,"is_corresponding":false},{"id":853549,"name":"Daniel Chubb","orcid":"0000-0002-3813-0981","position":5,"is_corresponding":false},{"id":883539,"name":"Charlie N. Saunders","orcid":"0000-0001-7221-1358","position":6,"is_corresponding":false},{"id":883540,"name":"Philip Smith","orcid":"0000-0002-9306-1747","position":7,"is_corresponding":false},{"id":883541,"name":"Huairen Zhang","orcid":"0000-0001-7646-9305","position":8,"is_corresponding":false},{"id":883542,"name":"Yasemin Cole","orcid":"0000-0002-9492-5885","position":9,"is_corresponding":false},{"id":68913,"name":"James Larkin","orcid":"0000-0001-5569-9523","position":10,"is_corresponding":false},{"id":518147,"name":"Lisa Browning","orcid":"0000-0003-4254-333X","position":11,"is_corresponding":false},{"id":230077,"name":"Samra Turajlic","orcid":"0000-0001-8846-136X","position":12,"is_corresponding":false},{"id":230059,"name":"Kevin Litchfield","orcid":"0000-0002-3725-0914","position":13,"is_corresponding":false},{"id":254457,"name":"Richard S. Houlston","orcid":"0000-0002-5268-0242","position":14,"is_corresponding":false},{"id":760961,"name":"Eamonn R. Maher","orcid":"0000-0002-6226-6918","position":15,"is_corresponding":false},{"id":18896,"name":"Bryndís Yngvadóttir","orcid":"0000-0002-7429-2961","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T00:23:48.622830Z","pmid":"35441217","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}