Familial melanoma

Familial melanoma

What do I need to know?

Rare, highly penetrant Penetrance refers to the proportion of people with a particular genetic variant who will go on to develop the condition. For example, people carrying an autosomal dominant variant may not always develop the condition – this is called ‘incomplete penetrance’. If a condition is 100% penetrant, an individual will definitely develop the condition. If penetrance is 80%, most but not all individuals will develop the condition. Other genes and lifestyle factors, such as diet, exercise and smoker status, may affect the penetrance of some conditions. For more information, refer to MedlinePlus’ ‘What are reduced penetrance and variable expressivity?’ variants in a small number of genes (CDKN2A and CDK4) are associated with familial melanoma. These variants show an autosomal dominant inheritance Autosomal recessive conditions affect either sex, and often occur in the absence of any family history. Recessive conditions or traits appear when an individual inherits two copies of pathogenic variants in the same gene (one from each parent). Parents of a child with an autosomal recessive condition are usually asymptomatic carriers. The affected child has two copies of the particular gene change. The recurrence risk of autosomal recessive conditions is one in four for each pregnancy. Wide variability in clinical expression is common in many autosomal recessive conditions. Autosomal recessive conditions are more common when the parents are consanguineous. pattern. Only 1–2% of melanomas are due to pathogenic variants A pathogenic variant is a genetic variant that increases an individual’s susceptibility or predisposition to certain diseases. Pathogenic variants are also known as mutations. in these genes.

Having a first-degree relative with melanoma approximately doubles an individual’s risk of developing melanoma. Having relatives who are affected with multiple melanomas or at a younger age further increases the risk of developing melanoma.

Genetic testing

Genetic testing for CDKN2A gene variants Gene variants are small DNA sequence changes (ie additions, duplications, deletions, substitutions). These variants can have a range of effects: some may cause disease (pathogenic variant), while others do not cause disease but may modify an individual’s risk of disease (i.e may increase risk or provide a protective effect). The vast majority of gene variants are benign and do not result in disease but rather contribute to the differences between people. may be offered through specialist genetics or dermatology services in individuals with:

• Three or more relatives affected by melanoma on the same side of the family

Other features within the family:

• multiple melanomas in the same person
• melanoma diagnosed <40 years of age
• ocular melanoma
• pancreatic cancer

Validated polygenic risk scores for melanoma are commercially available and may be used to provide individualised information about melanoma risk. Their precise role in risk-based melanoma prevention and screening in Australia is yet to be determined.

When should I refer?

Individuals with more than one family member with melanoma should be referred to a dermatologist for clinical risk management.

Individuals with three or more relatives affected with melanoma and/or pancreatic cancer in the family should be referred to a family cancer clinic for genetic risk assessment.

Other considerations

Individuals with familial melanoma should be encouraged to advise family members to discuss their risk with their general practitioner (GP).