Co-occurrence of Pathogenic VHL and FANCC Germline Mutations in a Patient with Multisystem Neoplasia: A Case Report

Abstract von Hippel-Lindau (VHL) disease is a multisystem hereditary cancer syndrome caused by pathogenic variants in the VHL gene. Fanconi anemia complementation group C (FANCC) mutations are primarily associated with autosomal recessive Fanconi anemia (FA), but emerging evidence suggests a role in cancer predisposition even in heterozygous states. We report a 49-year-old Indian male with a long-standing history of central nervous system (CNS) hemangioblastomas and clear cell renal cell carcinoma (ccRCC), consistent with a classical VHL phenotype. Germline next-generation sequencing revealed pathogenic variants in both VHL (c.484C > T; p.Cys162Arg) and FANCC (c.826delA; p.Ile276*) genes. This case underscores the clinical complexity arising from dual molecular diagnoses. The VHL mutation is well-established as pathogenic, disrupting hypoxia-inducible factor regulation. The FANCC variant is a novel frameshift mutation predicted to result in premature truncation. While FANCC mutations are associated with FA in biallelic states, heterozygous carriers may have an increased malignancy risk. Comprehensive germline testing plays a critical role in complex phenotypes. Our case highlights the importance of surveillance, family screening, and emerging therapies like belzutifan in VHL. Further research is warranted to clarify the oncogenic potential of heterozygous FANCC variants.