Genetic counselling for common diseases, cancer susceptibility as paradigm

Abstract

Inherited component of cancer risk may be subdivided into rare, high penetrance genes conferring a strong susceptibility to certain cancers, which may account for about 5% of cases, uncommon, moderately penetrant genes conferring a moderate risk increase, and common polymorphisms which alter disease risk a small amount. • There are two types of genetic test for a strong inherited cancer susceptibility: a test for a mutation in an affected person (diagnostic) and a test for a known mutation in a family in an unaffected relative (predictive). • There may be one of three outcomes of a diagnostic genetic test: (1) The test may reveal a pathogenic mutation, which explains the disease in the proband and allows genetic tests to be offered to their close relatives. (2) The test may not reveal a pathogenic mutation, so no genetic test will be available for close relatives, and no explanation will have been found for the cancer. However, other (probably lower penetrance) predisposing genes could still have contributed to the aetiology of the cancer. (3) A sequence change may be detected whose significance may not be clear, necessitating further tests to clarify this. Such variants are not uncommon. • Genetic counselling for predictive and diagnostic testing follows clear protocols, including pre-test counselling with a discussion of the important consequences and options for management of a mutation carrier, the interpretation of results, and insurance and other relevant issues. The genetic test is followed by a results appointment and post-test counselling and support, as appropriate. • Genetic testing for moderate risk susceptibility gene mutations are not in common use in the health service because the relative risk conferred is generally insufficient to warrant alterations in clinical management.