More is not always better: clinical genetics of familial breast cancer in the era of massively enhanced sequencing capacities

In the past decade, DNA sequencing has vastly increased in throughput, as well as vastly declined in cost per base pair with the emergence of massively parallel next-generation sequencing technology. This rapid technological progress has made clinical genetic testing of multigene panels and even whole exomes instead of single genes technically feasible, and is widespread practice today. This shift in genetic testing has increased the complexity and challenges in sequence interpretation, and the rate at which new sequence variants are being discovered continues to outpace the rate at which these data can be understood and turned into biological and clinical insight. Moreover, methods for classification of these variants differ between clinical laboratories, and are not as well studied and developed as the sequencing methods to identify them. To address these challenges, the American College of Medical Genetics and Genomics (ACMG) has released updated standards and guidelines for the classification of sequence variants (1). Recently, these guidelines were successfully applied to the classification of variants identified by multigene panel sequencing in families affected by hereditary breast cancer (2).