Table 1. Summary of genes with mutations related to pheochromocytoma/paraganglioma formation.

Gene	Gene name	Function	Classification	Malignancy risk	Relative mutation frequency		Predominant tumor site	Related hereditary disease
					somatic	germline
VHL	Von Hippel Lindau	regulates HIF1a and HIF2a proteasomal degradation	Group 1, neuronal precursor cell pathway	low	high	high	pheochromocytomas/paragangliomas	von Hippel Lindau syndrome, type1, type2
SDHA	Succinate dehydrogenase subunit A	core subunit of the mitochondrial protein complex SDH	Group 1, neuronal precursor cell pathway	NA	NA	medium	paragangliomas	PGL5, Leigh syndrome (Homozygous germline mutations)
SDHB	Succinate dehydrogenase subunit B	core subunit of the mitochondrial protein complex SDH	Group 1, neuronal precursor cell pathway	high	NA	high	paragangliomas/pheochromocytomas	PGL4 syndrome
SDHC	Succinate dehydrogenase subunit C	structural subunit of the mitochondrial protein complex SDH	Group 1, neuronal precursor cell pathway	low	NA	medium	paragangliomas	PGL3 syndrome
SDHD	Succinate dehydrogenase subunit D	structural subunit of the mitochondrial protein complex SDH	Group 1, neuronal precursor cell pathway	low	NA	high	paragangliomas/pheochromocytomas	PGL1 syndrome
SDHAF2	Succinate dehydrogenase complex assembly factor 1	participates in SDH complex formation	Group 1	NA	NA	low	paragangliomas	PGL2 syndrome
FH	Fumarate hydratase	catalyzes the conversion of fumarate to malate in the Krebs cycle	Group 1	high	low	low	paragangliomas/pheochromocytomas	leiomyomatosis, renal cancer
PHD2	Prolyl hydroxylase domain protein 2	participates in the regulation of HIF activity	Group 1	NA	NA	low	paragangliomas/pheochromocytomas	NA
HIF2α	Hypoxia-inducible factor 2-alpha	transcription factor of the bHLH–PAS protein family	Group 1	NA	high	low	paragangliomas/pheochromocytomas	NA
IDH1	Isocitrate dehydrogenase 1	converts isocitrate to α-ketoglutarate	Group 1	NA	low	NA	paragangliomas	NA
MDH2	Malate dehydrogenase 2	participates in oxidation of malate to oxaloacetate in the Krebs cycle	Group 1	NA	NA	low	paragangliomas	NA
RET	Rearranged during transfection	transmembrane tyrosine kinase receptor for extracellular signal molecules of the GDNF family	Group 2, neuronal precursor cell pathway	low	high	high	pheochromocytomas/paragangliomas (rare)	Sipple syndrome
NF1	Neurofibromin 1	inhibits the GTPase HRAS and disrupts the RAS signaling pathway	Group 2, neuronal precursor cell pathway	high - of malignant tumors	very high	medium	pheochromocytomas/paragangliomas (rare)	neurofibromatosis type 1
TMEM127	Transmembrane protein 127	unknown function	Group 2	low	NA	low	pheochromocytomas	NA
MAX	MYC associated factor X	transcription factor participates in regulation of cell proliferation, differentiation, death	Group 2	low	medium	low	pheochromocytomas/paragangliomas	NA
KIF1B	Kinesin family member 1B	transports mitochondria (KIF1Bα) and synaptic vesicle precursors (KIF1Bβ)	Group 2	NA	low	low	pheochromocytomas	NA
MEN1	Multiple endocrine neoplasia 1	plays role in gene expression regulation	Group 2	low	NA	low	pheochromocytomas/paragangliomas (rare)	multiple endocrine neoplasia type 1
GDNF	Glial cell line derived neurotrophic factor	ligand of the tyrosine kinase receptor RET	no Group	NA	low	NA	pheochromocytomas	Hirschsprung's disease
HRAS	Harvey rat sarcoma viral oncogene homolog	molecular switch conveying signals from the membrane to the nucleus	no Group	NA	high	medium	pheochromocytomas/paragangliomas	Costello syndrome
KRAS	Kirsten rat sarcoma viral oncogene homolog	molecular switch conveying signals from the membrane to the nucleus	no Group	NA	NA	NA	pheochromocytomas	Noonan syndrome
GNAS	Guanine nucleotide binding Protein	complex imprinted locus on chromosome 20q13.3	no Group	NA	low	NA	pheochromocytomas/paragangliomas	NA
TP53	Tumor suppressor protein p53	plays role in transcription activation, interaction with DNA, oligomerization	Common oncogene	NA	low	NA	paragangliomas	hereditary cancer types
p16	Cyclin-dependent kinase inhibitor gene	regulates p53 and retinoblastoma pathways	Common oncogene		NA	NA	pheochromocytomas
BAP1	Breast cancer associated protein 1	participates in regulation of the cell cycle, cell differentiation, DNA damage response	Common oncogene	NA	very low	very low	paragangliomas	tumor predisposition syndrome
ATRX	Alpha thalassemia/mental retardation syndrome X-linked	plays an important role in supporting telomere and chromosome integrity	Common oncogene	NA	low	NA	pheochromocytomas/paragangliomas	X-linked alpha thalassemia mental retardation syndrome
KMT2D	Lysine (K)-specific methyltransferase 2D/mixed-lineage leukemia 2, MLL2	participates in regulation of DNA accessibility by histone H3K4 methylation	Common oncogene	NA	low	NA	pheochromocytomas	Kabuki syndrome
BRAF	Murine sarcoma viral (v-raf) oncogene homolog B1	participates in activation of the RAS/RAF/ERK signal pathway	Common oncogene	NA	NA	NA	pheochromocytomas
BRCA1	Breast cancer 1 gene	oncosupressor, plays role in cell cycle regulation, differentiation, DNA damage response	Common oncogene	NA	NA	NA	pheochromocytomas	breast, ovarian cancer
BRCA2	Breast cancer 2 gene	oncosupressor, plays role in cell cycle regulation, differentiation, DNA damage response	Common oncogene	NA	NA	NA	pheochromocytomas	breast, ovarian cancer