PatientID: None

KindredID: 1

Case: F, 52Y0M, Danish

DiseaseAssertion: Breast carcinoma

FamilyInfo: The patient had three sons all of whom carried the VHL mutation. Two of the sons were asymptomatic and one had renal cell carcinoma. The affected son also had a P2P mutation and he had a child who was found to have the VHL mutation (P2P). The patient's mother had the mutation but was also asymptomatic. See Figure 1 for family pedigree.

CasePresentingHPOs: HP:0003002 (Breast carcinoma)

CaseHPOFreeText: The patient had breast cancer at age 34.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P81S (c.241C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

CAID: N/A

gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:P81S (c.241C>T)

MultipleGeneVariants: N/A

KindredID: E

GroupSize: 15

DiseaseAssertion: VHL

GroupNumberMales: 6

GroupNumberFemales: 9

GroupEthnicity: N/A

GroupAgeRange: 27-55

GroupInfo: In family E, 12 patients were diagnosed with VHL disease, and 3 patients passed away before this family was screened. The missense mutation p.V170D was found in this family. It is not specified in this paper which family members were genotyped and found to have this mutation.

GroupPresentingHPOs: HP:0006880; HP:0000543, HP:0002666; HP:0001737; HP:0011732; HP:0000238; HP:0000648; HP:0005584; HP:0010797; HP:0003002; HP:0009711; HP:0002350; HP:0001407 (Cerebellar hemangioblastoma, Optic disc pallor, Pheochromocytoma, Pancreatic cysts, Abnormality of adrenal morphology, Hydrocephalus, Optic atrophy, Renal cell carcinoma, Hemangioblastoma, Breast carcinoma, Retinal capillary hemangioma, Cerebellar cyst, Hepatic cysts)

GroupHPOFreeText: Overall, family E suffers from VHL clinical type 2B. Phenotypic information for each family member is described in detail in the paper (pages 557-558.) Briefly, Patient I-1 died of of renal cell carcinoma at age 55Y. Patients II-2 and II-4 died of obstructive hydrocephalus caused by a cerebellar haemangioblastoma at the ages of 33 and 39 years respectively. The proband (patient II-7), presented with obstructive hydrocephalus caused by a cerebellar hemangioblastoma, a secondary optic atrophy, no retinal angiomas at age 55. He also has pancreatic and adrenal cysts. His elder brother (patient II-3) has a small angioma on one optic disc, bilateral renal carcinomas, and cysts in cerebellum, adrenals and pancreas. His elder sister (patient II-5) has pale optic discs, an intra-medullary hemangioblastoma, unilateral renal carcinoma, bilateral phaeochromocytomas and a unilateral mamma carcinoma. Patient III-4, has a small parapapillary angioma and an ora serrata angioma with a dilated feeder artery and draining vein present in one eye. He also has cerebellar haemangioblastomas, bilateral phaeochromocytomas, renal carcinomas, pancreatic cysts, liver cysts and medullary haemangioblastomas. Patient III-6 has pale optic discs and suffers from a small cerebellar haemangioblastoma. Patient III-7 had bilateral phaeochromocytomas. Patient III-8 developed a very small angiomain one eye at the age of 28 years. She also has bilateral renal carcinomas. Patient III-10 has retinal angiomas in both eyes and also suffers from bilateral renal carcinomas and medullary haemangioblastomas. Patient III-11 suffers from a uni-lateral renal carcinoma. Patient III-12 has optic atrophy secondary to obstructive hydrocephalus because of a cerebellar haemangioblastoma and a macular retinal angioma that detached from the retina but is still attached to the optic disc. At age 27 new angiomas started to develop in both retinas including a recurrent angioma in the left macula with exudation in the posterior pole .She also suffered from a haemangioblastoma of the medulla oblongata and bilateral renal carcinomas. Patient III-13 developed retinal angiomas in one eye at the age of 32 years. Family member III-14 has pale optic discs with a normal neurological examination.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170D (c.509T>A) Note: the cDNA change is not explicitly reported in this paper and was extrapolated from the reported protein coding change.

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625256, https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/?new_evidence=true

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V170D (c.509T>A)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 1

Case: F, 54Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Son (id:1) with the same variant, presenting with cerebellar hemangioblastoma at age 18, spinal hemangioblastomas at ages 19 and 31 and renal cysts but the age of onset for these is not noted. Father (id: 3) presented with cerebellar hemangioblastoma at age 65. Paternal uncle (id: 4) presented with prostate cancer at age 65. Paternal grandfather (id: 5) presented with cerebellar hemangioblastomas at age 69. Mother and daughter did not have the mutation. Her father was not tested. No family history of retinal capillary hemangiomas or pheochromocytoma.

CasePresentingHPOs: HP:0006880; HP:0005584; HP:0003002 (Cerebellar hemangioblastoma, Renal cell carcinoma, Breast carcinoma)

CaseHPOFreeText: Bilateral breast cancer at age 46 and 49. First cancer was diagnosed at the age of 46 in her right breast. The patient was treated by mastectomy with postoperative chemotherapy (CMF). Histopathological examination revealed invasive ductal breast carcinoma. A metastasis in 1 axillary lymph node was found. There was no evidence of distant metastases. Three years later, at the age of 49, she was diagnosed with cancer of her left breast. It was an invasive ductal carcinoma. There was no evidence for lymph-node or distant metastases. At present, 9 and 6 years after treatment of the breast cancers there is no evidence of breast cancer recurrence. However at age of 54, lesions typical for VHL disease including cerebellar haemangioblastoma and renal cell carcinoma were diagnosed in the patient.

CaseNotHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1 (pedigree) and Table 1 (phenotype and age of onset data).

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: Germline, FANCD2, Partial Deletion

PatientID: 2

KindredID: 1

Case: F, 54Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Son (id:1) with the same variant, presenting with cerebellar hemangioblastoma at age 18, spinal hemangioblastomas at ages 19 and 31 and renal cysts but the age of onset for these is not noted. Father (id: 3) presented with cerebellar hemangioblastoma at age 65. Paternal uncle (id: 4) presented with prostate cancer at age 65. Paternal grandfather (id: 5) presented with cerebellar hemangioblastomas at age 69. Mother and daughter did not have the mutation. Her father was not tested. No family history of retinal capillary hemangiomas or pheochromocytoma.

CasePresentingHPOs: HP:0006880; HP:0005584; HP:0003002 (Cerebellar hemangioblastoma, Renal cell carcinoma, Breast carcinoma)

CaseHPOFreeText: Bilateral breast cancer at age 46 and 49. First cancer was diagnosed at the age of 46 in her right breast. The patient was treated by mastectomy with postoperative chemotherapy (CMF). Histopathological examination revealed invasive ductal breast carcinoma. A metastasis in 1 axillary lymph node was found. There was no evidence of distant metastases. Three years later, at the age of 49, she was diagnosed with cancer of her left breast. It was an invasive ductal carcinoma. There was no evidence for lymph-node or distant metastases. At present, 9 and 6 years after treatment of the breast cancers there is no evidence of breast cancer recurrence. However at age of 54, lesions typical for VHL disease including cerebellar haemangioblastoma and renal cell carcinoma were diagnosed in the patient.

CaseNotHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1 (pedigree) and Table 1 (phenotype and age of onset data).

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: Germline, FANCD2, Partial Deletion