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We analyzed sequence data from NSNSCLC\u2010affected cousin pairs belonging to high\u2010risk lung cancer pedigrees identified in a genealogy of Utah linked to statewide cancer records to identify rare, shared candidate predisposition variants. Variants were tested for association with lung cancer risk in UK Biobank. Evidence for linkage with lung cancer was also reviewed in families from the Genetic Epidemiology of Lung Cancer Consortium. Protein prediction modeling compared the mutation with reference. We sequenced NSNSCLC\u2010affected cousin pairs from eight high\u2010risk lung cancer pedigrees and identified 66 rare candidate variants shared in the cousin pairs. One variant in the <jats:italic>FGF5<\/jats:italic> gene also showed significant association with lung cancer in UKBiobank. This variant was observed in 3\/163 additional sampled Utah lung cancer cases, 2 of whom were related in another independent pedigree. Modeling of the predicted protein predicted a second binding site for SO<jats:sub>4<\/jats:sub> that may indicate binding differences. This unique study identified multiple candidate predisposition variants for NSNSCLC, including a rare variant in <jats:italic>FGF5<\/jats:italic> that was significantly associated with lung cancer risk and that segregated with lung cancer in the two pedigrees in which it was observed. <jats:italic>FGF5<\/jats:italic> is an oncogenic factor in several human cancers, and the mutation found here (W81C) changes the binding ability of heparan sulfate to FGF5, which might lead to its deregulation. These results support <jats:italic>FGF5<\/jats:italic> as a potential NSNSCLC predisposition gene and present additional candidate predisposition variants.<\/jats:p>","DOI":"10.1002\/ijc.34510","type":"journal-article","created":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T07:37:00Z","timestamp":1678779420000},"page":"364-372","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A rare <i>FGF5<\/i> candidate variant (rs112475347) for predisposition to nonsquamous, nonsmall\u2010cell lung cancer"],"prefix":"10.1002","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2602-3668","authenticated-orcid":false,"given":"Lisa A.","family":"Cannon\u2010Albright","sequence":"first","affiliation":[{"name":"Genetic Epidemiology, Department of Internal Medicine University of Utah School of Medicine  Salt Lake City Utah USA"},{"name":"Huntsman Cancer Institute  Salt Lake City Utah USA"},{"name":"George E. 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