TABLE 1.

Germline mutations associated with melanocytic tumors. The relevant gene and its function, clinical phenotype, and histopathological features of melanoma are summarized here.

Genea	Gene/protein function	Phenotype	Histopathologic features or most common histopathologic subtype of melanoma
Cyclin dependent kinase inhibitor 2A (CDKN2A)	• Tumor suppressor • Two main alternate transcripts: (a) p16 inhibits CDK4 and phosphorylation of RB; (b) p14ARF inhibits HDM2 and ubiquitination of p53	• Melanocytic nevi, melanoma, pancreatic, upper GI, and respiratory cancers; astrocytoma, neurofibromas and schwannomas (mutation affecting p14ARF)	• Superficial spreading melanoma • Pigmentation, pagetoid scatter, and spindle cell morphology in vertical growth phase
Cyclin dependent kinase 4 (CDK4)	• Oncogene • Inhibits binding of p16 tumor suppressor leading to phosphorylation of RB and cell cycle progression	• Melanocytic nevi, melanoma, pancreatic cancer	• Superficial spreading melanoma • Pigmentation and pagetoid scatter
Telomerase reverse transcriptase (TERT)	• Telomerase reverse transcriptase, a component of telomerase • Normally repressed in postnatal somatic cells leading to shortening of telomeres	• Melanoma, melanocytic nevi, other reported cancers (ovarian, renal cell, bladder, breast, and bronchial cancer)	• Nodular and superficial spreading melanoma
Protection of telomeres 1 (POT1)	• Constituent of shelterin complex that regulates telomere processing and stability	• Melanoma, other reported cancers (glioma, chronic lymphocytic leukemia, colorectal, breast, and lung cancers)	• Superficial spreading melanoma
ACD shelterin complex subunit and telomerase recruitment factor (ACD)	• Constituent of shelterin complex that regulates telomere processing and stability	• Melanoma, other reported cancers (breast, ovarian, cervical, uterine, thyroid, colon, lung, renal, urinary, prostate and esophageal cancers, lymphomas and leukemias)	• Superficial spreading melanoma, and lentigo maligna melanoma
TERF2 interacting protein (TERF2IP)	• Constituent of shelterin complex that regulates telomere processing and stability	• Melanoma, other reported cancers (breast, ovarian, cervical, uterine, thyroid, colon, lung, renal, urinary, prostate and esophageal cancers, lymphomas and leukemias)	• Superficial spreading melanoma, and lentigo maligna melanoma
Melanocyte inducing transcription factor (MITF)	• A melanocytic lineage-specific transcription factor, regulating differentiation, proliferation and survival of melanocytes	• Melanoma, renal cell carcinoma • Darker hair, fair skin, and non-blue eye color	• Amelanotic • Thicker tumors (in some populations) • Nodular melanoma
Melanocortin-1 receptor (MC1R)	• G protein coupled receptor for melanocyte-stimulating hormone • Controls melanogenesis and thus skin and hair color	• Melanoma • Red hair, freckling, light skin, and UV sensitivity (loss-of-function variants)	• Anatomic site (arms; in carriers of more than one high-risk variant)
BRCA1 associated protein 1 (BAP1)	• Deubiquitinating enzyme, BRCA1 binding partner • Implicated in chromatin modulation, transcriptional regulation, and DNA damage repair	• BAP1-inactivated nevi, uveal melanoma, cutaneous melanoma, mesothelioma, and renal cell carcinoma • Other reported tumors (basal cell carcinoma, meningioma, cholangiocarcinoma, breast, lung, pancreatic, and thyroid cancer)	BAP1-inactivated nevi: • Exclusively or predominantly intradermal • Associated common nevus component often present (a combined nevus) • Epithelioid melanocytes with round to oval vesicular nuclei and abundant amphophilic cytoplasm • May show smaller epithelioid cells without abundant eosinophilic cytoplasm • May show rhabdoid features

^aGene symbols and nomenclature obtained from the HUGO Gene Nomenclature Committee.