Development, technical validation, and clinical application of a multigene panel for hereditary gastrointestinal cancer and polyposis.

INTRODUCTION: Recent advances in technology and research are rapidly changing the diagnostic approach to hereditary gastrointestinal cancer (HGIC) syndromes. Although the practice of clinical genetics is currently transitioning from targeted criteria-based testing to multigene panels, important challenges remain to be addressed. The aim of this study was to develop and technically validate the performance of a multigene panel for HGIC.

METHODS: CGT-colon-G14 is an amplicon-based panel designed to detect single nucleotide variants and small insertions/deletions in 14 well-established or presumed high-penetrance genes involved in HGIC. The assay parameters tested were sensitivity, specificity, accuracy, and inter-run and intra-run reproducibility. Performance and clinical impact were determined using 48 samples of patients with suspected HGIC/polyposis previously tested with the targeted approach.

RESULTS: The CGT-colon-G14 panel showed 99.99% accuracy and 100% inter- and intra-run reproducibility. Moreover, panel testing detected 1 actionable pathogenic variant and 16 variants with uncertain clinical impact that were missed by the conventional approach because they were located in genes not previously analyzed.

CONCLUSION: Introduction of the CGT-colon-G14 panel into the clinic could provide a higher diagnostic yield than a step-wise approach; however, results may not always be straightforward without the implementation of new genetic counseling models.