Hereditary cancer

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

• Cancer patients who meet relevant clinical criteria for tumour predisposition syndromes
• Patients with unusual age of onset, with a rare cancer, with multiple cancer diseases, or with suspicious family history
• Patients whose tumours have histopathological and/or molecular pathological characteristics suspicious for a causal germline alteration, e.g., mismatch-repair-deficiency or MSI-high tumour, loss of expression of a corresponding protein
• At-risk relatives of a proband with a known pathogenic germline variant, for cascade testing

Testing is typically requested by clinical geneticists but can be ordered by any other physician treating a patient with suspected tumor predisposition syndrome.

Germline testing is used when a personal or family cancer history suggests hereditary predisposition. Results of genetic testing can inform about management und surveillance decisions for patients and carriers and can even guide treatment options.

• A pathogenic or likely pathogenic variant identifies an inherited predisposition and names the gene involved. Penetrance is incomplete: a positive result does not mean cancer will develop.
• A variant of uncertain significance (VUS) is an unclear finding: evidence is insufficient to classify it as likely benign or likely pathogenic. A VUS does not guide management; reanalysis can be offered as evidence accumulates.
• In other patients, no pathogenic variant is detected. 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 expert curated gene-specific ACMG/AMP criteria if available, or to general criteria.

When a pathogenic germline variant is identified, risk-adapted surveillance and, where indicated, risk-reducing options can be discussed for the carrier; the evidence base differs between syndromes and organ systems. Relatives can be offered predictive testing. Where a syndrome presents in childhood, testing of minors and surveillance from an early age are addressed in counselling.

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, so please to check access in your region.

Testing uses based single-gene and multi-gene panels to identify single nucleotide variants (SNVs) and copy number variations (CNVs).