{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T10:44:30Z","timestamp":1790419470314,"version":"4.1.0"},"reference-count":31,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U24CA248265"],"award-info":[{"award-number":["U24CA248265"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA244729"],"award-info":[{"award-number":["R01CA244729"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000892","name":"Prostate Cancer Foundation","doi-asserted-by":"publisher","award":["20CHAS01"],"award-info":[{"award-number":["20CHAS01"]}],"id":[{"id":"10.13039\/100000892","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2022,2,15]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Germline variants in fumarate hydratase (<jats:italic>FH<\/jats:italic>) are associated with autosomal dominant (AD) hereditary leiomyomatosis and renal cell cancer (HLRCC) and autosomal recessive (AR) fumarase deficiency (FMRD). The prevalence and cancer penetrance across different <jats:italic>FH<\/jats:italic> variants remain unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A database containing 120,061 records from individuals undergoing cancer germline testing was obtained. <jats:italic>FH<\/jats:italic> variants were classified into 3 categories: AD HLRCC variants, AR FMRD variants, and variants of unknown significance (VUSs). Individuals with variants from these categories were compared with those with negative genetic testing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>FH<\/jats:italic> variants were detected in 1.3% of individuals (AD HLRCC, 0.3%; AR FMRD, 0.4%; VUS, 0.6%). The rate of AD HLRCC variants discovered among reportedly asymptomatic individuals without a clear indication for HLRCC testing was 1 in 2668 (0.04%). In comparison with those with negative genetic testing, the renal cell carcinoma (RCC) prevalence was elevated with AD HLRCC variants (17.0% vs 4.5%; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.01) and VUSs (6.4% vs 4.5%; <jats:italic>P<\/jats:italic>\u00a0=\u00a0.02) but not with AR FMRD variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The prevalence of HLRCC discovered incidentally on germline testing is similar to recent population carrier estimates, and this suggests that this is a relatively common cancer syndrome. Compared with those with negative genetic testing, those with VUSs had an elevated risk of RCC, whereas those with AR FMRD variants did not.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.33997","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T12:05:50Z","timestamp":1635768350000},"page":"675-684","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Fumarate hydratase variant prevalence and manifestations among individuals receiving germline testing"],"prefix":"10.1002","volume":"128","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4045-4229","authenticated-orcid":false,"given":"Eric","family":"Lu","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology University of California Los Angeles Los Angeles California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0849-7018","authenticated-orcid":false,"given":"Kathryn 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