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Germline variants in the fumarate hydratase (<jats:italic>FH<\/jats:italic>) gene predispose to HLRCC. Identifying germline pathogenic <jats:italic>FH<\/jats:italic> variants enables lifetime renal cancer screening and genetic testing for family members. In this report, we present a <jats:italic>FH<\/jats:italic> missense variant (c.1039T&gt;C (p.S347P)), initially classified as a variant of uncertain significance. Clinical assessment, histopathological findings, molecular genetic studies, and enzymatic activity studies support the re\u2010classification of the <jats:italic>FH<\/jats:italic> c.1039T&gt;C variant to \u201cpathogenic\u201d based on ACMG\/AMP criteria. Further insights into pathological recognition of FH\u2010deficient renal cancer are discussed and should be recognized. This study has shown how (a) detailed multi\u2010disciplinary analyses of a single variant can reclassify rare missense variants in <jats:italic>FH<\/jats:italic> and (b) careful pathological review of renal cancers is obligatory when HLRCC is suspected.<\/jats:p>","DOI":"10.1002\/gcc.23221","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T13:28:15Z","timestamp":1707398895000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Segregation, immunohistochemical, molecular and functional analyses classify a novel missense variant in fumarate hydratase (<scp><i>FH<\/i><\/scp>) as pathogenic"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1556-5851","authenticated-orcid":false,"given":"Lydia","family":"Ouchene","sequence":"first","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine McGill University  Montr\u00e9al Quebec 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