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Renal cell carcinoma (RCC) occurs in several hereditary cancer disorder syndromes, and RCC\u2010related MPT comprise individuals with multiple primary renal tumours (MPRT) and those with RCC plus a non\u2010renal tumour (MPT:RCC + X). Excluding rare syndromic causes, knowledge of the genetic architecture of MPRT\/MPT:RCC + X is limited. To inform diagnostic approaches to MPRT\/MPT:RCC + X, we present the findings of comprehensive genomic analysis in 534 individuals. The presence\/absence of variants in cancer susceptibility genes (CSGs) from exome\/genome sequencing was then correlated with data on age, sex, tumour types, and RCC histopathology in 93 participants with MPRT and 441 with MPT:RCC + X. 7.5% of participants with MPRT and 6.1% in participants with MPT:RCC + X had germline CSG pathogenic variants, and the diagnostic yields increased to 9.4% and 10.4%, respectively, in cases with RCC &lt;66\u2009years. Excluding participants with environmental carcinogen\u2010linked cancers increased the diagnostic yield in MPT:RCC + X to 12.9%. Pathogenic variants were mostly in CSGs known to predispose to RCC, but in almost half of these cases, typical extrarenal tumours were not present. In conclusion, our findings support amended eligibility criteria for diagnostic testing in MPRT and wider eligibility criteria for testing in MPT:RCC + X, with RCC &lt;66\u2009years.<\/jats:p>","DOI":"10.1002\/ijc.70085","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T13:20:56Z","timestamp":1755868856000},"page":"2532-2543","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Clinical and genetic features of multiple primary tumours cohorts with a renal cell carcinoma: Implications for molecular genetic investigations"],"prefix":"10.1002","volume":"157","author":[{"given":"Huairen","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, School of Clinical Medicine University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryndis","family":"Yngvadottir","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Clinical Medicine University of Cambridge  Cambridge 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 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 UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma R.","family":"Woodward","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, and Division of Evolution, Infection and Genomics University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Whitworth","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Clinical Medicine University of Cambridge  Cambridge 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 UK"},{"name":"Aston Medical School, College of Health and Life Sciences Aston University  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/esmoopen-2017-000172"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.12-1-20"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010024\u201052,659\u20103"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-021-08766-9"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.04.013"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21492"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2022.08.019"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431\u2010024\u201001628\u20105"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddac089"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.22893"},{"key":"e_1_2_12_12_1","unstructured":"CaulfieldM FowlerT BillinsT et al.The National Genomics Research and Healthcare Knowledgebase: Amendment to the 100 000 Genomes Project Protocol v4. 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