Sixteen patients were screened for variants in one or more of the RCC predisposition genes VHL, FH, FLCN, MET or SDHB (Table 2). No pathogenic variants were found in FH, FLCN, MET or SDHB, but we did find a start codon variant (c.3G>A, p.Met1Ile) and a missense variant (c.631A>C, p.Met211Leu) in VHL in a patient from cohort 2 (Fig 3). Both VHL variants are classified as class 3 variants (VUS) according to the classification guidelines from IARC [26].Open in a separate windowFig 3Pedigree of family 6002.The arrow indicates the proband. The age of RCC-onset and histological subtype the renal tumor is listed below the proband (III:3). A start codon VUS (c.3G>A, p.Met1Ile) and a missense variant (c.631A>C, p. Met211Leu) in VHL and a intron variant (c.1729+8T>C) in BAP1 was identified in a peripheral blood sample from the proband. The proband’s maternal uncle (II:1) was diagnosed with testicular cancer.
PatientID: III:1
KindredID: 6002
Case: M, 28Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Maternal uncle (II:1) had a history of testicular cancer but no genetic data was available.
CohortInfo: Patients met at least one of the criteria: RCC < forty years of age or bilateral or multifocal RCC < sixty years of age or family history of RCC or three relatives with RCC, melanoma or mesothelioma (at least one case of RCC) or patients diagnosed with RCC and melanoma. Family history of RCC is defined as two or more first-degree relatives with RCC. Patients with a previously identified pathogenic variant in a renal cancer predisposition gene were not included. Patient inclusion took place from February 2014 to January 2015. This patient was grouped in “Group 1” where only one family member was affected by renal cell carcinoma (n=20).
CasePresentingHPOs: HP:0006770 (Clear cell renal cell carcinoma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: The patient has been through the national screening program for putative VHL, which includes MRI of the cerebrum, spinal medulla and abdomen, neurological examination, auditory tests, ocular examination and blood work for chromogranin A and metanephrines, with normal results.
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Figure 3
Variant: p.M1I (c.3G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 135406, https://www.ncbi.nlm.nih.gov/clinvar/variation/135406/
CAID: N/A
gnomAD: 0.00007043, https://gnomad.broadinstitute.org/variant/3-10183534-G-A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: M1I (c.3G>A)
MultipleGeneVariants: Germline, VHL, c.631A>C (p.Met211Leu)
MultipleGeneVariants: Germline, BAP1, c.1729+8T>C