Diagnostic outcomes of concurrent DNA and RNA sequencing in individuals undergoing hereditary cancer testing

Personalized surveillance, prophylaxis, and cancer treatment options for individuals with hereditary cancer predisposition are informed by results of germline genetic testing. Improvements to genomic technology, such as the availabilty of RNA sequencing, may increase identification of individuals eligible for personalized interventions by improving the accuracy and yield of germline testing. In a diagnostic study including 43,524 individuals undergoing hereditary cancer testing, simultaneous RNA sequencing was associated with increased diagnostic positive yield and decreased inconclusive rate of multigene panel testing for germline cancer predisposition. RNA-dependent classifications were made in 17.1% of splicing variants classified as pathogenic (1.9% of any variant classified as pathogenic), and 71.1% of splicing variants of uncertain significance (2.1% of any VUS) resolved as benign. The authors conclude that RNA sequencing provides an opportunity to more accurately identify individuals with hereditary cancer susceptibility by increasing detection and improving classification of disease-causing variants.