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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\u2009000 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\u00a0years (\u00b112 SD), range: 13\u201388\u00a0years; 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 \u2018hot VUSs\u2019) 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 &amp;lt;50\u00a0years. 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\u2009=\u20090.0019). 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.<\/jats:p>","DOI":"10.1093\/hmg\/ddac089","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T07:14:50Z","timestamp":1649920490000},"page":"3001-3011","source":"Crossref","is-referenced-by-count":37,"title":["Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases"],"prefix":"10.1093","volume":"31","author":[{"given":"Bryndis","family":"Yngvadottir","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, School of Clinical Medicine, University of Cambridge , Cambridge, CB2 0QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avgi","family":"Andreou","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Clinical Medicine, University of Cambridge , Cambridge, CB2 0QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laia","family":"Bassaganyas","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Clinical Medicine, University of Cambridge , Cambridge, CB2 0QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey","family":"Larionov","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Clinical Medicine, University of Cambridge , Cambridge, CB2 0QQ , UK"},{"name":"School of Water, Energy and Environment, Cranfield University , Cranfield, MK43 0AL , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex J","family":"Cornish","sequence":"additional","affiliation":[{"name":"Division of Genetics and Epidemiology, The Institute of Cancer Research , London, SW7 3RP , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Chubb","sequence":"additional","affiliation":[{"name":"Division of Genetics and Epidemiology, The Institute of Cancer Research , London, SW7 3RP , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlie N","family":"Saunders","sequence":"additional","affiliation":[{"name":"Division of Genetics and Epidemiology, The Institute of Cancer Research , London, SW7 3RP , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip S","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Clinical Medicine, University of Cambridge , Cambridge, CB2 0QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huairen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Clinical Medicine, University of Cambridge , Cambridge, CB2 0QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasemin","family":"Cole","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Clinical Medicine, University of Cambridge , Cambridge, CB2 0QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genomics England","family":"Research Consortium","sequence":"additional","affiliation":[{"name":"Genomics England, Queen Mary University of London , Dawson Hall, Charterhouse Square, London, EC1M 6BQ , UK"},{"name":"William Harvey Research Institute, Queen Mary University of London , London, EC1M 6BQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Larkin","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Renal and Skin Units, The Royal Marsden NHS Foundation Trust , London, SW3 6JJ , UK"},{"name":"Melanoma and Kidney Cancer Team, The Institute of Cancer Research , London, SW7 3RP , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Browning","sequence":"additional","affiliation":[{"name":"Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust , John Radcliffe Hospital, Oxford, OX3 9DU , UK"},{"name":"NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust , Oxford, OX4 2PG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samra","family":"Turajlic","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Renal and Skin Units, The Royal Marsden NHS Foundation Trust , London, SW3 6JJ , UK"},{"name":"Melanoma and Kidney Cancer Team, The Institute of Cancer Research , London, SW7 3RP , UK"},{"name":"Cancer Dynamics Laboratory, The Francis Crick Institute , London, NW1 1AT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Litchfield","sequence":"additional","affiliation":[{"name":"Department of Oncology, University College London Cancer Institute , Paul O\u2019Gorman Building, London, WC1E 6DD , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard S","family":"Houlston","sequence":"additional","affiliation":[{"name":"Division of Genetics and Epidemiology, The Institute of Cancer Research , London, SW7 3RP , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6226-6918","authenticated-orcid":false,"given":"Eamonn R","family":"Maher","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Clinical Medicine, University of Cambridge , Cambridge, CB2 0QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,20]]},"reference":[{"key":"2022090105181771300_ref1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21442","article-title":"Cancer 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