N20: A New Approach In Panel Testing For Hereditary Cancer: Phenotype-Derived With Opportunistic Screening Of Mismatch Repair Genes And BRCA1 And BRCA2

L. Feliubadaló1, 2, A. López3, J. del Valle1, A. Stradella1, O. Díez4, S. Gutiérrez4, G. Capellá1, 2, M. Pineda1, 2, J. Balmaña3, J. Brunet1, 2, J. C. Lazaro1, 2

1 – Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, L’Hospitalet de Llobregat, Barcelona, Spain. 2 – Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain. 3 – High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. 4 – Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain


Aim: Multigene panels provide a powerful tool for analyzing several genes simultaneously. We evaluated the frequency of pathogenic variants (PVs) in customized pre-defined phenotype-based panels and compared it to the yield obtained in the analysis of an extended 24-gene panel. We also investigated the mutational yield of opportunistic screening of mismatch repair (MMR) and BRCA1/2 genes.

Method: A total of 1205 unrelated probands with clinical suspicion of hereditary cancer were screened for germline mutations using next generation sequencing panels: 205 HNPCC-suspected, 883 HBOC-suspected, 73 polyposis-suspected and 44 with other/multiple clinical suspicion.

Results: Our phenotype-driven panel identified 150 carriers of PVs (12%). Opportunistic screening additionally identified 5 MSH6, 1 BRCA1 and 1 BRCA2 carriers. The additional analysis of our extended 24-gene panel provided 26 additional PVs (3%), including 4 out of 51 individuals harboring MMR-proficient tumors (2 CHEK2 and 2 ATM). Multiplex panel unmasked discrepancies between MMR immunohistochemistry pattern and the germline mutation.

Conclusion: Comprehensive panels increase the mutational yield by 3% over a phenotype-approach. Opportunistic screening of highly penetrant genes leads to a significant straightforward identification of MMR and BRCA1/2 mutation carriers, and endorses the model of opportunistic testing of genes with clinical utility under a standard genetic counseling process.