PatientID: 21

KindredID: 12

Case: F, 27Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated.

CasePresentingHPOs: HP:0002893; HP:0002666 (Pituitary adenoma, Pheochromocytoma)

CaseHPOFreeText: Pituitary adenoma presented at age 27. Pheochromocytoma age of presentation unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX/RET/TMEM127/SDHA/SDHB/SDHC/SDHD/SDHAF2

PreviouslyPublished: N/A

SupplementalData: Table 1, Supplementary Table 6

Variant: p.D197N (c.589G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756524, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA351756524

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: D197N (c.589G>A)

MultipleGeneVariants: Germline, SDHA, c.91C>T (p.Arg31*)

PatientID: 89

KindredID: 89

Case: F, 39Y0M, Chinese (East Asian)

DiseaseAssertion: Paraganglioma

FamilyInfo: No family history.

CasePresentingHPOs: Paraganglioma (HP:0002668)

CaseHPOFreeText: retroperitoneal paraganglioma 6.8cm in size; metastatic. Age of diagnosis at 39Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P154S (c.460C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 486714 https://www.ncbi.nlm.nih.gov/clinvar/variation/486714

CAID: N/A

gnomAD: N/A

VariantEvidence: Described as a pathogenic variant, according to the ACMG guidelines at the time of publication.

MutationType: missense_variant;transition

CivicName: P154S (c.460C>T)

MultipleGeneVariants: N/A

PatientID: 92

KindredID: 92

Case: M, 31Y0M, Chinese (East Asian)

DiseaseAssertion: Assumed VHL

FamilyInfo: No family history.

CasePresentingHPOs: Pheochromocytoma; Paraganglioma (HP:0002666; HP:0002668)

CaseHPOFreeText: retroperitoneal paraganglioma and bilateral pheochromocytoma, with a biggest tumor size of 5cm. Age of onset and diagnosis at 9Y. 22 years later they were confirmed with a genetic mutation

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: Described as a pathogenic variant, according to the ACMG guidelines at the time of publication.

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 87

KindredID: 87

Case: M, 38Y0M, Chinese (East Asian)

DiseaseAssertion: Pheochromocytoma

FamilyInfo: No family history.

CasePresentingHPOs: Pheochromocytoma (HP:0002666)

CaseHPOFreeText: Pheochromocytoma symptomatic and diagnosed at age 36Y, 2.3cm in size. 2 years later he underwent PPGL genetic testing.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P138P (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206 https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: Described as a pathogenic variant, according to the ACMG guidelines at the time of publication.

MutationType: synonymous_variant; missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: paraganglioma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002668 (paraganglioma)

CaseHPOFreeText: Paraganglioma of the head and neck region (HNPGL): Right carotid body; nonsecreting paraganglioma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P81L (c.242C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 36899 https://www.ncbi.nlm.nih.gov/clinvar/variation/36899

CAID: N/A

gnomAD: 0.000004349 https://gnomad.broadinstitute.org/variant/3-10183773-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P81L (c.242C>T)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: paraganglioma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002668 (paraganglioma)

CaseHPOFreeText: Paraganglioma of the head and neck region (HNPGL): Left carotid body; nonsecreting paraganglioma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T152I (c.455C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351754382 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.455C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: T152I (c.455C>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)