Defining Pathogenic Variants in RASopathies

Pathogenic germline variants in the RAS/MAPK pathway genes cause phenotypically overlapping genetic syndromes called mastopathies. Even though these variants occur in different genes, they ultimately lead to the upregulation of the RAS/MAPK pathway, albeit through different genetic mechanisms. The shared clinical features among these syndromes impede accurate clinical diagnoses; therefore, genetic testing supports the correlation of a molecular diagnosis with a clinical diagnosis. This chapter reviews current approaches to defining pathogenic variation in the RASopathies using the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) variant guideline recommendations for a molecular diagnosis. These guidelines use gene knowledge like inheritance patterns and disease mechanisms to assess normal population data and case evidence. Systematic review of the different types of evidence available, their varying strength levels, and functional evidence in the context of the gene and its phenotypes is important to correctly classify a pathogenic variant in the RASopathies.