Here, we report a FH missense mutation c.1132G > A (p.E378K) in exon 8 that was never documented before as a germline mutation associated with HLRCC, that upgraded as likely pathogenic based on segregation analysis, molecular characterization of blood and tumors, and further in vitro functional study, which extended our knowledge about the pathogenic mutations of FH in an attempt to delineate the role of this gene in pathogenicity and carcinogenesis. Here, FH is linked to hereditary leiomyomatosis and renal cell cancer.