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Among these, the proband and an affected brother each had a heterozygous Ala45Thr variant in <jats:italic>SDHA<\/jats:italic>, a component of the succinate dehydrogenase (SDH) complex. SDH defects are associated with mitochondrial disorders and risk for various cancers; immunochemical analysis indicated loss of SDHB protein expression in the patient\u2019s tumor, compatible with SDH deficiency. Integrated analysis of public databases and structural predictions indicated that the two affected individuals also had additional variants in genes including <jats:italic>TGFB2<\/jats:italic>, <jats:italic>TRAP1<\/jats:italic>, <jats:italic>PARP1<\/jats:italic>, and <jats:italic>EGF<\/jats:italic>, each potentially relevant to cancer risk alone or in conjunction with the <jats:italic>SDHA<\/jats:italic> variant. In addition, allelic imbalances of <jats:italic>PARP1 <\/jats:italic>and <jats:italic>TGFB2<\/jats:italic> were detected in the tumor of the proband.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Together, these data suggest the possibility of risk associated with interaction of two or more variants.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.556","type":"journal-article","created":{"date-parts":[[2019,1,25]],"date-time":"2019-01-25T05:11:54Z","timestamp":1548393114000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Interaction of germline variants in a family with a history of early\u2010onset clear cell renal cell carcinoma"],"prefix":"10.1002","volume":"7","author":[{"given":"Emmanuelle","family":"Nicolas","sequence":"first","affiliation":[{"name":"Molecular Therapeutics Program Fox Chase Cancer Center Philadelphia 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