PatientID: DHPLC 1

KindredID: 1

Case: M, 51Y0M, Unknown Ethnicity

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient’s daughter (DHPLC 1) had a pheochromocytoma at 11Y. At 18Y, she had a pheochromocytoma in the contralateral adrenal gland and two concurrent paragangliomas of the abdominal aorta and urinary bladder. At 25Y, she was found to have a right frontal meningioma. A family history obtained from his daughter’s other parent, one son and one other daughter (not DHPLC 1) was uninformative. The patient’s relatives (except for his daughter) were normal both clinically and biochemically.

CasePresentingHPOs: HP:0001028; HP:0000277; HP:0009715; HP:0000107 (Angioma, abnormality of the mandible, papillary cystadenoma of the epididymis, renal cyst)

CaseHPOFreeText: The patient had an attenuated VHL phenotype caused by mosaicism which led to what initially appeared to be a de novo mutation in his daughter (DHPLC 3). The patient was found to have an angioma of the glans penis and had had surgery for a mandibular cyst and epididymal cystadenomas at age 43Y. Abdominal ultrasonography and total-body magnetic resonance imaging (MRI) conducted at the time of the study (51Y) revealed a 2.3-cm cyst in his right kidney. His blood pressure and levels of plasma free metanephrines, fractionated urinary metanephrines, chromogranin A were normal.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: p.R161Q (c.695G>A)

ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q(c.482G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 38Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo:

CasePresentingHPOs: HP:0002666; HP:0001028 (Pheochromocytoma, Hemangioma)

CaseHPOFreeText: Was diagnosed with bilateral pheochromocytoma resected when she was the age of 18 years. She presented several relapses, the most recent one at the age of 32, when she was also diagnosed with cerebral angioma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R82G (c.244C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1297059, https://www.ncbi.nlm.nih.gov/clinvar/variation/1297059/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R82G (c.244C>G)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 16Y0M, Ukrainian

DiseaseAssertion: Assumed VHL

FamilyInfo: Her brother (patient 2) also had polycythemia and was heterozygeous for the mutation. Mutation inherited from father. The father was not polycythemic, but his BFU-Es were hypersensitive to Epo.

CasePresentingHPOs: HP:0001901, HP:0005954, HP:0000077, HP:0001028 (polycythemia, pulmonary capillary hemangiomatosis, abnormality of the kidney, hemangioma )

CaseHPOFreeText: Patient had a hematocrit of 68%, erythropoietin level of 45 mIU/mL, and had hypersensitivity of erythroid progenitors to Epo. She was diagnosed with polycythemia of unknown duration; at the age of 10 years, a pulmonary angioma was found and treated by a coil embolization. She continued to be polycythemic. At the age of 15 years, an abdominal computed tomography (CT) scan revealed a left renal mass, which on nephrectomy was determined to be a subcapsular hemangioma; there was no evidence of an angioma elsewhere. One year after surgery, she still remains polycythemic but has no evidence of a new or recurrent tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D126Y(c.376G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2230 https://www.ncbi.nlm.nih.gov/clinvar/variation/2230/

CAID: CA020319 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.376G%3ET

gnomAD: N/A

VariantEvidence: Patient was heterozygous for the mutation.

MutationType: missense_variant;transversion

CivicName: D126Y(c.376G>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: A

Case: M, 61Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Positive: the patient’s sister also presented with the germline c.562C>G mutation, and metastatic lobular breast carcinoma. In a family pedigree, 10 additional members affected with cancer were displayed. This included both of their parents: father with lung cancer, mother with skin cancer, additional sister with breast cancer, brother with melanoma. Lastly, his two sons presented with skin cancer, however no description of their genotyping. See Fig. 3.

CasePresentingHPOs: HP:0006770; HP:0001028 (Clear cell renal cell carcinoma, hemangioma)

CaseHPOFreeText: He presented in 2012 (52Y) with worsening lower abdominal discomfort (CT scan revealed a right renal solid mass of renal cell carcinoma). A right renal nephrectomy was done, confirming ccRCC. 4 years later, new lung nodules and an enhancing lesion in the L1 vertebral body was found (metastatic ccRCC). Additionally, in 2020, a pancreatic lesion present on his scans was presumed to be a metastatic RCC lesion (consistent with an atypical hemangioma).

CaseNotHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, retinal capillary hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX/NF1/RET/SDHA/SHDB/SHDC/SDHD/SDHAF2/TMEM127 [133 genes evaluated by germline testing - Invitae]

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: p.L188V (c.562C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: In 2013, somatic next generation sequencing (NGS) testing using a panel of 447 cancer genes (OncoPanel, BWH Pathology, MA, USA) was performed on the resected renal specimen. This revealed the following variants: VHL p.Leu188Val (c.562C>G), CHEK2 p.Val395Leu (c.1183G>C), VHL p.Ala149Thr (c.445G>A) variant, and several copy number losses including a large single-copy deletion in 3p. 6 years later, germline testing revealed a heterozygous germline VHL p.Leu188Val variant, a CHEK2 and ERCC4 mutation.

ClinVarID: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: N/A

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L188V (c.562C>G)

MultipleGeneVariants: Somatic, VHL, c.445G>A (p.Ala149Thr)