Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels

Lídia Feliubadaló, Adrià López-Fernández, Marta Pineda, Orland Díez, Jesús del Valle, Sara Gutiérrez-Enríquez, Alex Teulé, Sara González, Neda Stjepanovic, Mónica Salinas, Gabriel Capellá, Joan Brunet, Conxi Lázaro, Judith Balmaña, Olga Campos, Estela Carrasco, Raquel Cuesta, Esther Darder, Neus Gadea, Carolina GómezElia Grau, Silvia Iglesias, Angel Izquierdo, Gemma Llort, Mireia Menéndez, Alejandro Moles-Fernández, Eva Montes, Xavier Muñoz, Matilde Navarro, Teresa Ramon y Cajal, Judit Sanz, Ares Solanes, Agostina Stradella, Eva Tornero, Sara Torres-Esquius, Noemí Tuset, Gisela Urgell, Angela Velasco

    Research output: Contribution to journalArticleResearch

    22 Citations (Scopus)


    © 2019 UICC Multigene panels provide a powerful tool for analyzing several genes simultaneously. We evaluated the frequency of pathogenic variants (PV) in customized predefined panels according to clinical suspicion by phenotype and compared it to the yield obtained in the analysis of our clinical research gene panel. We also investigated mutational yield of opportunistic testing of BRCA1/2 and mismatch repair (MMR) genes in all patients. A total of 1,205 unrelated probands with clinical suspicion of hereditary cancer were screened for germline mutations using panel testing. Overall, 1,048 females and 157 males were analyzed, mean age at cancer diagnosis was 48; 883 had hereditary breast/ovarian cancer-suspicion, 205 hereditary nonpolyposis colorectal cancer (HNPCC)-suspicion, 73 adenomatous-polyposis-suspicion and 44 with other/multiple clinical criteria. At least one PV was found in 150 probands (12%) analyzed by our customized phenotype-driven panel. Tumoral MMR deficiency predicted for the presence of germline MMR gene mutations in patients with HNPCC-suspicion (46/136 vs. 0/56 in patients with and without MMR deficiency, respectively). Opportunistic testing additionally identified five MSH6, one BRCA1 and one BRCA2 carriers (0.6%). The analysis of the extended 24-gene panel provided 25 additional PVs (2%), including in 4 out of 51 individuals harboring MMR-proficient colorectal tumors (2 CHEK2 and 2 ATM). Phenotype-based panels provide a notable rate of PVs with clinical actionability. Opportunistic testing of MMR and BRCA genes leads to a significant straightforward identification of MSH6, BRCA1 and BRCA2 mutation carriers, and endorses the model of opportunistic testing of genes with clinical utility within a standard genetic counseling framework.
    Original languageEnglish
    Pages (from-to)2682-2691
    JournalInternational Journal of Cancer
    Publication statusPublished - 15 Nov 2019


    • actionability
    • cancer susceptibility
    • germline cancer panel


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