Clinical Genomics: From Pathogenicity Claims to Quantitative Risk Estimates

Fifteen years after the Human Genome Project, genomic variants have been associated with disease risk and outcomes in thousands of publications. Based largely on this literature, physicians who order genetic testing receive reports that indicate whether "pathogenic" variants have been found. This information aspires to form the basis of precision medicine. Knowledge of pathogenic variants is expected to lead to optimal management of individuals as well as their families through recommendations about further screening, prevention, and tailored treatment. However, some suggest that current information on pathogenic variants is typically impossible to act on. This information is often unreliable and generally does not provide a quantitative measure of risk. The information the physician usually needs is the likelihood of disease among patients with the variant (penetrance), and an assessment of whether the genetic profile requires action or not. Here, Manral and Ioannidis discuss sharing the underlying data of genetic testing to develop more precise disease risk estimates and understand whether physicians should act on them.