Hereditary skin tumours

Genetic testing is clinically relevant for the following indications, including but not limited to:

• Three or more primary melanomas or melanoma cooccurring with pancreatic cancer in an individual or family, which points to
• Multiple clinically atypical naevi in an individual or family affected by melanoma
• Uveal or cutaneous melanoma with mesothelioma or
• Multiple or early-onset basal cell carcinomas, jaw keratocysts or childhood medulloblastoma
• Sebaceous adenoma, sebaceoma or sebaceous carcinoma, particularly with a personal or family history of Lynch-associated cancer
• with characteristic mucocutaneous lesions, particularly alongside PHTS-associated cancers in the individual or family
• Multiple cutaneous or plexiform neurofibromas
• At-risk relatives of a known variant carrier, for predictive testing

Genetic testing is used when an inherited skin-tumour syndrome is suspected from the tumour pattern or the family history. The probability of identifying a causative variant generally increases with multiple primary tumours, young onset, several affected relatives and syndrome-specific combinations of tumours. Because these syndromes are genetically heterogeneous, multigene testing may be appropriate when several genes could explain the presentation.

A pathogenic or likely pathogenic variant establishes the specific molecular diagnosis, identifying the causative gene and the associated tumour-predisposition syndrome. A variant of uncertain significance (VUS) is an unclear finding: current evidence is insufficient to classify it as likely benign or likely pathogenic, and reanalysis can be offered after a few years as evidence accumulates. In other cases, no pathogenic variant is detected in the analysed genes. The presence of a pathogenic variant cannot, however, be entirely excluded: the causative change may lie in a gene not yet linked to the condition, or in a regulatory region that current methods cannot reliably capture.

Each variant is classified according to ACMG/AMP criteria.

When a germline pathogenic variant is identified, syndrome-specific surveillance can be established, with structured skin examination and, depending on the syndrome, ophthalmological, renal, gastrointestinal or neurological monitoring. The finding also concerns relatives, who can be offered predictive testing, so that carriers enter surveillance and non-carriers may avoid it.

is an essential part of the testing process and is available both before and after testing. Our genetic counsellors conduct comprehensive family history assessments, explain the chosen testing methodology, its benefits, risks, and limitations, and provide guidance on result interpretation, management strategies, and recurrence risk. Counselling supports physicians in delivering informed care and helps patients and families make well-informed medical decisions. Availability of genetic counselling services may vary by country, so please to check for more information on access in your region.

Testing uses next-generation sequencing (NGS) based multi-gene panels.

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