Hereditary multi-tumour syndromes

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

• Individuals and families meeting the revised Chompret criteria for Li-Fraumeni syndrome
• Patients with a DICER1-spectrum sentinel tumour, such as pleuropulmonary blastoma, Sertoli-Leydig cell tumour or cystic nephroma
• Individuals with multiple primary tumours, unusually early-onset cancer, or a rare sentinel tumour suggestive of a predisposition syndrome
• At-risk relatives of a person with a known familial pathogenic variant, for predictive cascade testing

Testing is typically requested by clinical geneticists, medical and paediatric oncologists, and organ specialists.

Germline testing is considered when a personal or family tumour history meets established criteria, such as the revised Chompret criteria, or when the clinical presentation is suggestive of a predisposition syndrome. Confirming a pathogenic variant informs surveillance decisions and enables risk-adapted, often childhood-onset monitoring of confirmed carriers.

• 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 criteria.

A confirmed pathogenic variant enables risk-adapted, organ-specific tumour surveillance and, where indicated, risk-reducing measures appropriate to the identified syndrome. It guides treatment and reproductive counselling and carries familial implications: relatives can be offered predictive cascade testing, directing surveillance to carriers and reassuring non-carriers. Where syndromic features are present, multidisciplinary care can be coordinated.

is an important part of the testing process. It helps patients and families understand the test, interpret results, and make well-informed medical decisions, and it supports physicians in delivering informed care. Availability of genetic counselling services may vary by country. Please to check out access in your region.

Testing is performed using based multi-gene panels.

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