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In the index case and three relatives, germline genetic testing identified a heterozygous <jats:italic>TSC2<\/jats:italic> missense pathogenic variant [c.2714 G\u2009&gt;\u2009A, (p.Arg905Gln)], a rare TSC\u2010associated alteration which has previously been associated with a milder TSC phenotype. Whole\u2010exome sequencing of five RCCs from the index case and one RCC from his mother demonstrated either unique tumour\u2010specific deleterious second hits in <jats:italic>TSC2<\/jats:italic> or significant allelic imbalance at the <jats:italic>TSC2<\/jats:italic> gene locus (5\/6 RCCs). This study confirms the key tumourigenic role of tumour\u2010specific <jats:italic>TSC2<\/jats:italic> second hits in TSC\u2010associated RCCs and supports the notion that RCCLS may be strongly related to abnormalities of the mTOR pathway.<\/jats:p>","DOI":"10.1002\/cjp2.104","type":"journal-article","created":{"date-parts":[[2018,4,16]],"date-time":"2018-04-16T12:02:54Z","timestamp":1523880174000},"page":"167-174","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Atypical tuberous sclerosis complex presenting as familial renal cell carcinoma with leiomyomatous stroma"],"prefix":"10.1002","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2035-9048","authenticated-orcid":false,"given":"Isma\u00ebl","family":"Bah","sequence":"first","affiliation":[{"name":"Department of Pathology McGill University Health Centre Montreal QC 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