Biochemical characterization of the FH variant p.Lys414Glu reveals loss of enzymatic function and disrupted multimerization

Variants of uncertain significance (VUS) in fumarate hydratase ( FH ) complicate the diagnosis of hereditary leiomyomatosis and renal cell carcinoma (HLRCC). The FH VUS p.Lys414Glu has been reported in patients with HLRCC features but additional evidence is needed to support an interpretation of pathogenicity. Here we show that p.Lys414Glu is completely inactive, supporting a classification of pathogenic and providing critical evidence for clinical care and surveillance of patients with germline FH p.Lys414Glu.