Computational Approach Profiles Splicing, Reduces VUS in Hereditary Cancer Tests

In the Journal of Molecular Diagnostics, Invitae investigators consider the clinical consequences of hereditary cancer syndrome genetic tests that include messenger RNA splicing changes. Using its RNA sequencing-based "splice effect event resolver" (SPEER) workflow — established to interrogate germline genetic variants that disrupt such slicing, including those classified as variants of uncertain significance — the team identified dozens of cancer-related genes in more than 20,300 individuals. The SPEER analysis uncovered transcript splicing changes in 971 of the 3,563 individuals carrying variants expected to alter splicing and, in another 40 individuals, splicing changes linked to variants that were not already profiled. In the process, the author explain, they were also able to reclassify VUSs as pathogenic/likely pathogenic or as benign/likely benign in more than 6 percent of the 20,417 individuals considered. "By combining comprehensive DNA and RNA sequencing with the validated SPEER algorithm," they write, "we will continue to collect data from individuals referred for hereditary cancer syndrome testing, develop deeper insights into the clinical relevance of splicing alterations, and improve the interpretation of inherited DNA variants — leading to a further reduction of uncertainty for hereditary cancer gene testing."