Familial melanoma & melanoma predisposition syndromes

FAMMM; familial atypical multiple mole melanoma syndrome; CDKN2A-related melanoma; BAP1 tumour predisposition syndrome (BAP1-TPDS); MC1R variants

Around 5–10% of melanoma is familial. The strongest known predisposition genes are CDKN2A (the major contributor; encodes p16INK4a and p14ARF), CDK4, BAP1 and POT1. Recognising and referring families enables genetic confirmation, intensified surveillance, and screening for syndrome-specific extra-cutaneous malignancies.

CurrentLast reviewed 19 May 2026

Key points

Refer to clinical genetics if: ≥ 3 melanomas in a family across two generations; ≥ 2 primary melanomas in one individual at any age; melanoma + pancreatic cancer in the same individual or family; melanoma + uveal melanoma + mesothelioma + RCC (BAP1).

CDKN2A is the most commonly identified gene — penetrance varies by population (≈50% by age 50 in northern Europe). CDKN2A also confers increased pancreatic cancer risk.

BAP1-TPDS: cutaneous melanoma + uveal melanoma + mesothelioma + renal cell carcinoma + characteristic atypical Spitz tumours ('BAP1-inactivated melanocytic tumours' / BIMTs).

Surveillance is intensified — typically 3–6 monthly full-skin examination by trained clinician, dermoscopy, total-body photography, and patient self-examination training.

Pancreatic surveillance (annual MRI / EUS) is offered to CDKN2A carriers in some European programmes; UK practice variable — discuss with clinical genetics.

Predisposition genes

CDKN2A

The most commonly identified high-penetrance melanoma gene. Encodes two tumour suppressors (p16INK4a and p14ARF) via alternate reading frames. Melanoma penetrance ~50% by age 50, rising to up to ~70–90% by age 80, varying by population/latitude (highest in high-incidence regions such as Australia, intermediate in northern Europe, lowest in southern Europe).

Increased risk of pancreatic adenocarcinoma (~17–25% lifetime; some series 10–25%) and head & neck squamous cell carcinoma (well-established).

CDK4

Rare; melanoma risk similar to CDKN2A; no extra-cutaneous malignancy clearly attributed.

BAP1

BAP1-TPDS — cutaneous melanoma, uveal melanoma, mesothelioma, renal cell carcinoma, basal cell carcinoma, and characteristic 'BAP1-inactivated melanocytic tumours' (atypical Spitz-like, often dome-shaped pink papules).

POT1, ACD, TERF2IP, TERT

Telomere-pathway genes — emerging predisposition; growing role with NGS panels.

MC1R, MITF p.E318K

Common low-to-moderate penetrance variants. MC1R red-hair-colour variants increase melanoma risk modestly; MITF E318K confers melanoma + renal cell carcinoma risk.

When to refer to clinical genetics

UK criteria (variable by region; discuss with local genetics service):

≥ 3 melanomas in a family (any generation; ≥ 2 first-degree).
≥ 2 primary melanomas in one individual at any age. Young age strengthens suspicion but is not required.
Melanoma + pancreatic cancer in same individual or family.
Melanoma + uveal melanoma + mesothelioma in same individual or family (BAP1).
Atypical Spitz tumour with BAP1 loss on IHC.
Melanoma + renal cell carcinoma (BAP1, MITF).

Surveillance

Cutaneous

3–6 monthly full-skin examination by trained clinician (dermatology / specialist nurse) from teenage years.
Dermoscopy at each visit; total-body photography for naevus mapping where available.
Patient self-examination training; partner-assisted exam.
Sun protection from infancy; absolute sunbed avoidance.

Pancreatic (CDKN2A)

Annual MRI / MRCP and / or EUS in selected programmes; coordinate with hereditary GI cancer service.

Ophthalmic (BAP1)

Annual dilated fundoscopy from teenage years for uveal melanoma surveillance.

Renal (BAP1, MITF)

Annual renal ultrasound or MRI from age 30 in BAP1 carriers (variable practice).

Management of melanoma in carriers

Standard surgical management per NICE NG14 (margins, SLNB) — but surveillance after the first melanoma is intensified due to high second-primary risk. Adjuvant therapy decisions follow standard pathways (NICE TAs).

References

Soura E et al. Hereditary melanoma: update on syndromes and management — genetics of familial atypical multiple mole melanoma syndrome. J Am Acad Dermatol; 2016;74:395–407.

Carbone M et al. BAP1 and cancer. Nat Rev Cancer; 2013;13:153–9.

UK Cancer Genetics Group. Recommendations for the management of CDKN2A-related familial melanoma. (Periodically updated.)