{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T12:12:21Z","timestamp":1792239141936,"version":"4.4.0"},"reference-count":39,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2020,5,15]],"date-time":"2020-05-15T00:00:00Z","timestamp":1589500800000},"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":["1K08CA207845\u201001"],"award-info":[{"award-number":["1K08CA207845\u201001"]}],"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":["R01 HG008126"],"award-info":[{"award-number":["R01 HG008126"]}],"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":["UM1 HG006504"],"award-info":[{"award-number":["UM1 HG006504"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2020,8,15]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Hereditary leiomyomatosis and renal cancer (HLRCC) is a cancer syndrome associated with a germline mutation in fumarate hydratase (<jats:italic>FH<\/jats:italic>). The syndrome is associated with cutaneous and uterine leiomyomas, and some patients develop a lethal form of kidney cancer. This study provides estimates for the <jats:italic>FH<\/jats:italic> carrier frequency and kidney cancer penetrance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data sets containing sequencing data for the <jats:italic>FH<\/jats:italic> gene were used: the 1000 Genomes Project (1000GP) and the Exome Aggregation Consortium (ExAC). Alterations in the <jats:italic>FH<\/jats:italic> gene were characterized on the basis of different variant risk tiers: 1) ClinVar annotated variants, 2) loss\u2010of\u2010function alterations, and 3) highly impactful missense alterations. The cumulative incidence of <jats:italic>FH<\/jats:italic> alterations overall and by different world populations was evaluated in 1000GP and ExAC. A lifetime penetrance of HLRCC kidney cancer risk was generated with 3 estimates of the annual incidence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The overall allele frequencies of tier 1 to 3 <jats:italic>FH<\/jats:italic> alterations in the ExAC and 1000GP data sets were 2.54 \u00d7 10<jats:sup>\u20133<\/jats:sup> (1 in 393) and 1.20 \u00d7 10<jats:sup>\u20133<\/jats:sup> (1 in 835), respectively. There were differences in the allele frequencies of <jats:italic>FH<\/jats:italic> alterations between world populations. Based on various estimates of the percentage of kidney cancers with <jats:italic>FH<\/jats:italic> alterations, the lifetime kidney cancer penetrance for carrier estimate 3 in ExAC was 1.7% to 5.8%.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:italic>FH<\/jats:italic> alterations are common and are carried by approximately 1 in 1000 individuals according to the more conservative estimates. The lifetime kidney cancer penetrance appears lower than previously estimated. Although databases are not population cohorts, they provide a useful quantitative estimate of rare variants with low penetrance.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.32914","type":"journal-article","created":{"date-parts":[[2020,5,16]],"date-time":"2020-05-16T02:24:09Z","timestamp":1589595849000},"page":"3657-3666","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer"],"prefix":"10.1002","volume":"126","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2065-3570","authenticated-orcid":false,"given":"Brian","family":"Shuch","sequence":"first","affiliation":[{"name":"Department of Urology and Radiology and Biomedical Imaging Yale School of Medicine New Haven Connecticut"},{"name":"Department of Urology David Geffen School of Medicine University of California Los Angeles Los Angeles California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shantao","family":"Li","sequence":"additional","affiliation":[{"name":"Program in Computational Biology and Bioinformatics Yale University New Haven Connecticut"},{"name":"Department of Molecular Biophysics and Biochemistry Yale University New Haven Connecticut"},{"name":"Department of Computer Science Yale University New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harvey","family":"Risch","sequence":"additional","affiliation":[{"name":"Division of Chronic Disease Epidemiology Yale School of Public Health New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjit S.","family":"Bindra","sequence":"additional","affiliation":[{"name":"Department of Therapeutic Radiology Yale University New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick 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