Fumarate hydratase c.914T > C (p.Phe305Ser) is a pathogenic variant associated with hereditary leiomyomatosis and renal cell cancer syndrome

Mol Genet Genomic Med. 2020 Aug;8(8):e1293. doi: 10.1002/mgg3.1293. Epub 2020 May 28.

Abstract

Background: Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC), caused by heterozygous germline pathogenic variants in the FH, confers an increased risk for cutaneous and uterine leiomyomas and renal cancer.

Methods: About 13,722 advanced cancer patients, including 560 with renal cell carcinoma, had germline analysis performed in the context of tumor-normal sequencing under an IRB approved protocol.

Results: We report two unrelated individuals with early onset kidney cancer who both carried the c.914C > T (p.Phe305Ser) germline variant in the FH. Both tumors exhibited loss of FH staining by immunohistochemistry and/or positive 2SC staining. Subsequent familial testing discovered that a daughter of a proband who carried the variant had both cutaneous and uterine leiomyomas.

Conclusion: This combination of evidence suggests that the FH c.914C > T (p.Phe305Ser) is pathogenic for HLRCC.

Keywords: carcinoma; fumarate hydratase; leiomyomatosis; mutation; renal cell.

Publication types

  • Case Reports

MeSH terms

  • Female
  • Fumarate Hydratase / genetics*
  • Germ-Line Mutation
  • Humans
  • Leiomyomatosis / genetics*
  • Leiomyomatosis / pathology
  • Male
  • Middle Aged
  • Mutation, Missense
  • Neoplastic Syndromes, Hereditary / genetics*
  • Neoplastic Syndromes, Hereditary / pathology
  • Pedigree
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Uterine Neoplasms / genetics*
  • Uterine Neoplasms / pathology

Substances

  • Fumarate Hydratase

Supplementary concepts

  • Hereditary leiomyomatosis and renal cell cancer