Enhanced detection and characterization of germline structural variants in cancer predisposition genes via genome...

Germline pathogenic variants in cancer predisposition genes are found in approximately 10% of all cancer cases. Although multigene panel testing is the current first-tier approach for detecting variants in these genes, it has limitations in identifying and characterizing copy-number variants and other structural variants (SVs). Genome sequencing (GS) provides a more uniform coverage throughout the genome, thereby offering a more comprehensive method for copy-number variant and SV detection; however, its diagnostic utility in genetic testing for cancer predisposition remains underexplored.

In this study, we performed GS on 33 patients with previously identified germline SVs in cancer predisposition genes, including 25 deletions, 7 duplications, and 1 mobile element insertion.

Using 2 SV callers in the DRAGEN pipeline, GS achieved 100% sensitivity in detecting these SVs. Moreover, GS revealed additional insights not available through previous clinical testing in 9 (27%) cases, including identifying a complex SV, clarifying structural configuration of intragenic duplications, and refining breakpoints at base-pair resolution.

Taken together, our findings support the utility of GS as the sequencing backbone for germline genetic testing of cancer predisposition genes with improved detection, characterization, and clinical interpretation of SVs.