Due to recurrent hemangioblastomas, a29-year-old patient without familial history of VHL disease was diagnosed to be at risk for the disease. Histopathological examination of a small renal mass identified a clear cell tumor with a G1 grading. Genetic characterization of the germline and of the renal tumor was performed. Polymerase chain reaction/single strand conformation polymorphism (PCR/SSCP) analysis with primers from the VHL gene identified a deletion of a single nucleotide in exon 2 in the patient's germline and in the tumor, but not in the DNA of his parents. This deletion therefore must be a de novo mutation. Comparative genome hybridization (CGH) and fluorescence in situ hybridization (FISH) analysis of the G1 tumor with differentially labelled yeast artifical chromosome (YAC) clones showed loss of 3p and of the 3p26 signals, respectively. In conclusion, we identified a de novo germline mutation in the VHL gene of a young patient and a somatic chromosome 3p loss at the homologous chromosome 3 in his renal tumor. Our results suggest a recessive mode of inactivation of the VHL gene, providing solid evidence for its tumor-suppressor gene characteristics. Our data show the diagnostic potential of genetic testing, especially in patients without VHL family history. Furthermore, the findings of homozygous inactivation of the VHL gene in a G1 tumor support the notion that the inactivation of the VHL gene is an early event in tumorigenesis of renal cell carcinoma.
PatientID: Proband
KindredID: 1
Case: M, 29Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: No other family members presented with any signs of VHL disease. The patient’s aunt died from breast cancer at 46Y, the grandfather died of leukemia at 56Y.
CasePresentingHPOs: HP:0009713; HP:0006770; HP:0001737; HP:0005562 (Spinal hemangioblastoma, Clear cell renal cell carcinoma, Pancreatic cysts, Multiple renal cysts)
CaseHPOFreeText: Presented with recurrent spinal hemangioblastomas. Ultrasonography and computed tomography showed pancreatic and renal cysts and a renal mass. Histology after surgery to resent the renal tumor showed clear cell renal cell carcinoma.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.F148Lfs*11 (c.444del)
LegacyVariant: c.653del
CaseProblemVariantFreeText: N/A
ClinVarID: 223212, https://www.ncbi.nlm.nih.gov/clinvar/variation/223212/
CAID: N/A
gnomAD: N/A
VariantEvidence: Sequencing revealed one nucleotide was deleted from the pentameric thymidines nucleotides 653–657 of exon 2 of the VHL gene, predicted to result in a stop codon, in both constitutional blood and tumor samples. All other family members tested, including his 34-year-old sister, did not show any alteration of the gene, either by SSCP analysis or by sequencing. Based on the description of the pentameric thimidines at 653-657, it was concluded that the authors reported the variant according to legacy nomenclature (AF010238.1). This was mapped to p.Phe148Leufs*11 (c.444del) according to the reference sequence NM_000551.3. Homozygous inactivation of the VHL gene in a G1 tumor support the notion that the inactivation of the VHL gene is an early event in tumorigenesis of renal cell carcinoma.
MutationType: deletion; minus_1_frameshift_variant
CivicName: F148Lfs*11 (c.444del)
MultipleGeneVariants: N/A