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Condition report · Cancer

Hereditary Melanoma

Whole genome sequencing evaluates all melanoma and skin cancer predisposition genes (CDKN2A, CDK4, MC1R, BAP1, POT1, TERT, MITF), providing comprehensive hereditary skin cancer risk assessment.

A condition report looks for rare variants known to cause the conditions it covers.

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About this condition

Melanoma

A malignant, usually aggressive tumor composed of atypical, neoplastic melanocytes.

Approximately 5-10% of melanoma is familial. CDKN2A/p16 (chromosome 9p21.3) is the highest-penetrance melanoma gene: pathogenic variants confer 60-90% lifetime melanoma risk (population and UV-exposure dependent). CDKN2A carriers also have 13-22x increased pancreatic cancer risk. CDK4 is a rarer high-penetrance melanoma gene. MC1R (melanocortin-1 receptor) red hair/fair skin variants (R151C, R160W, D294H) confer 2-4x melanoma risk each, with compound heterozygotes at higher risk.

BAP1 tumor predisposition syndrome causes uveal (ocular) melanoma, mesothelioma, and cutaneous melanocytic BAP1-mutated atypical intradermal tumors (MBAITs). POT1, TERT promoter, and MITF E318K are additional melanoma susceptibility genes identified through family studies.

Clinical implications: CDKN2A carriers require total-body skin examinations every 3-6 months and annual dermoscopy/photography. MC1R genotyping can identify individuals at elevated risk who don't have classic red-hair phenotype (R151C carriers can have brown hair). Sun protection counseling guided by MC1R genotype is an emerging precision prevention strategy.

MC1R variants increase melanoma risk 2-4x even in people who DON'T have red hair. Many MC1R carriers have brown hair and tan skin but carry elevated genetic melanoma risk invisible to clinical assessment.

What your report covers

The 3 conditions we analyse

Melanoma

A malignant, usually aggressive tumor composed of atypical, neoplastic melanocytes. Most often, melanomas arise in the skin (cutaneous melanomas) and include the following histologic subtypes: superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, and lentigo maligna melanoma. Cutaneous melanomas may arise from acquired or congenital melanocytic or dysplastic nevi. Melanomas may also arise in other anatomic sites including the gastrointestinal system, eye, urinary tract, and reproductive system. Melanomas frequently metastasize to lymph nodes, liver, lungs, and brain.

What a diagnosis changes

Total-body skin exams every 3-6 months (CDKN2A); dermoscopy; MC1R-guided sun protection; BRAF+MEK inhibitors for BRAF-mutant melanoma; immunotherapy (anti-PD-1); pancreatic screening for CDKN2A; cascade testing

Also known as

malignant melanoma; melanoma (disease); melanoma, malignant

Includes 69 related subtypes ↓
  • acral lentiginous melanoma
  • adult leptomeningeal melanoma
  • amelanotic melanoma
  • amelanotic skin melanoma
  • anal melanoma
  • balloon cell malignant melanoma
  • CDK4 linked melanoma
  • cervix melanoma
  • childhood malignant melanoma
  • choroid epithelioid cell melanoma
  • choroid mixed cell melanoma
  • choroid necrotic melanoma
  • choroid spindle cell melanoma
  • ciliary body epithelioid cell melanoma
  • ciliary body mixed cell melanoma
  • ciliary body spindle cell melanoma
  • cutaneous melanoma
  • desmoplastic melanoma
  • digestive system melanoma
  • epithelioid cell melanoma
  • epithelioid cell uveal melanoma
  • esophageal melanoma
  • eyelid melanoma
  • familial melanoma
  • gallbladder melanoma
  • intermediate cell type choroid melanoma
  • intermediate cell type ciliary body melanoma
  • intermediate cell type iris melanoma
  • intermediate cell type uveal melanoma
  • iris melanoma
  • iris spindle cell melanoma
  • lentigo maligna melanoma
  • leptomeningeal melanoma
  • malignant breast melanoma
  • malignant choroid melanoma
  • malignant ciliary body melanoma
  • malignant conjunctival melanoma
  • malignant cornea melanoma
  • malignant melanoma of the mucosa
  • medium/large size posterior uveal melanoma
  • melanoma in congenital melanocytic nevus
  • melanoma, malignant familial intraocular
  • melanomatosis
  • meningeal melanomatosis
  • metastatic melanoma
  • mixed cell uveal melanoma
  • mixed epithelioid and spindle cell melanoma
  • mucosal melanoma
  • necrotic uveal melanoma
  • nodular malignant melanoma
  • non-cutaneous melanoma
  • ocular melanoma
  • ocular melanoma with extraocular extension
  • ovarian melanoma
  • pediatric leptomeningeal melanoma
  • posterior uveal melanoma
  • primary melanoma of the central nervous system
  • rectum malignant melanoma
  • retinal melanoma
  • scrotum melanoma
  • small size posterior uveal melanoma
  • spinal cord melanoma
  • spindle cell intraocular melanoma
  • spindle cell melanoma
  • spitzoid melanoma
  • superficial spreading melanoma
  • uveal melanoma
  • vaginal melanoma
  • vulvar melanoma
MONDO:0005105Orphanet 411533MedGen 9944

Susceptibility to familial cutaneous melanoma

Autosomal dominant

Inherited melanoma susceptibility caused by variants in genes such as CDKN2A, CDK4, MITF and POT1.

What a diagnosis changes

Regular full skin examinations, sun protection and, for CDKN2A carriers, consideration of pancreatic surveillance.

Genes analysed

Also known as

hereditary cutaneous melanoma (disease); melanoma, cutaneous malignant

Includes 10 related subtypes ↓
  • melanoma, cutaneous malignant, susceptibility to, 1
  • melanoma, cutaneous malignant, susceptibility to, 2
  • melanoma, cutaneous malignant, susceptibility to, 3
  • melanoma, cutaneous malignant, susceptibility to, 4
  • melanoma, cutaneous malignant, susceptibility to, 5
  • melanoma, cutaneous malignant, susceptibility to, 6
  • melanoma, cutaneous malignant, susceptibility to, 7
  • melanoma, cutaneous malignant, susceptibility to, 8
  • melanoma, cutaneous malignant, susceptibility to, 9
  • tumor predisposition syndrome 3
MONDO:0024462MedGen 1388845

Familial atypical multiple mole melanoma syndrome

Autosomal dominant

Many atypical moles with a high risk of melanoma, often caused by CDKN2A variants that also raise pancreatic cancer risk.

What a diagnosis changes

Regular full skin examinations and, where a CDKN2A variant is found, consideration of pancreatic cancer surveillance.

Genes analysed

Also known as

B-K mole syndrome; familial atypical mole melanoma syndrome; familial atypical mole syndrome; familial atypical multiple mole melanoma-pancreatic carcinoma syndrome; familial Clark nevus syndrome; familial dysplastic nevus syndrome; FAMM syndrome; FAMM-PC syndrome; FAMMM syndrome; melanoma-pancreatic cancer syndrome

Includes 1 related subtype ↓
  • melanoma-pancreatic cancer syndrome
MONDO:0018453Orphanet 404560MedGen 389220

Why whole genome sequencing

Melanoma risk assessment based on skin color alone misses MC1R carriers without typical phenotype. Genetic testing provides objective risk assessment independent of appearance.

CDKN2A carriers need dermatologic surveillance every 3-6 months, plus pancreatic cancer screening

CDKN2A confers 60-90% melanoma risk AND 13-22x pancreatic cancer risk. Identification triggers both intensive dermatologic surveillance and pancreatic cancer screening (MRI/EUS). Without genetic testing, the pancreatic cancer risk component is never addressed.

MC1R genotyping identifies hidden melanoma risk: brown-haired carriers need enhanced sun protection

MC1R R151C carriers can have brown hair, hazel eyes, and some tanning ability, but still carry 2-4x melanoma risk. Clinical assessment alone would not identify these individuals as high-risk. WGS reveals MC1R genotype, enabling personalized sun protection counseling based on genetic rather than phenotypic risk.

Other cancer conditions

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