{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T05:03:11Z","timestamp":1789534991564,"version":"build-2803163510"},"reference-count":53,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Germline Whole-Exome Sequencing (WES) has emerged as a powerful genomic approach for investigating Hereditary Cancer predisposition through the comprehensive analysis of coding regions across the genome. Although multigene panels currently represent the standard diagnostic approach for Hereditary Cancer assessment, a substantial proportion of high-risk individuals and families remain molecularly unexplained. In this setting, germline WES may serve as a valuable second-tier strategy by identifying pathogenic variants in genes not routinely included in conventional testing panels and by addressing part of the unresolved \u201cmissing heritability\u201d observed across Hereditary Cancer syndromes. Increasing evidence supports its application in hereditary breast and ovarian cancer, Lynch-like syndrome, colorectal polyposis, hereditary diffuse gastric cancer, and ovarian cancer predisposition, where WES has contributed to the identification of additional susceptibility genes and improved molecular characterization. Beyond Hereditary Cancer diagnostics, exome-based approaches have also been explored for tumour profiling, homologous recombination deficiency (HRD) assessment, biomarker discovery, and therapeutic stratification. However, despite its significant potential, the clinical implementation of WES remains challenging because of the high burden of variants of uncertain significance (VUS), difficulties in variant interpretation, incidental findings, and the need for robust functional validation of candidate genes. This review critically examines the current evidence supporting the clinical utility of germline WES in Hereditary Cancer syndromes, focusing on the clinical scenarios in which WES may provide meaningful additional information beyond multigene panels, its diagnostic yield, limitations, and future perspectives in precision oncology.<\/jats:p>","DOI":"10.3390\/genes17091102","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:39:24Z","timestamp":1789137564000},"page":"1102","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Utility of Germline Whole-Exome Sequencing Beyond Multigene Panels in Hereditary Cancer"],"prefix":"10.3390","volume":"17","author":[{"given":"Anastasia","family":"Dell\u2019Elice","sequence":"first","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Neurosciences, Imaging and Clinical Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Human Sciences, Law, and Economics, Telematic University \u201cLeonardo Da Vinci\u201d (UNIDAV), Torrevecchia Teatina, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6226-8086","authenticated-orcid":false,"given":"Lucia","family":"Lombardi","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Neurosciences, Imaging and Clinical Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9056-2825","authenticated-orcid":false,"given":"Federico","family":"Anaclerio","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Neurosciences, Imaging and Clinical Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Palmarini","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Neurosciences, Imaging and Clinical Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Canale","sequence":"additional","affiliation":[{"name":"Breast Unit, P.O. \u201cG. Bernabeo\u201d, 66026 Ortona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6356-8866","authenticated-orcid":false,"given":"Lorenzo","family":"Secondi","sequence":"additional","affiliation":[{"name":"Breast Unit, P.O. \u201cG. Bernabeo\u201d, 66026 Ortona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregorio","family":"Stratta","sequence":"additional","affiliation":[{"name":"Breast Unit, P.O. \u201cG. Bernabeo\u201d, 66026 Ortona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Vitali","sequence":"additional","affiliation":[{"name":"Breast Unit, P.O. \u201cG. Bernabeo\u201d, 66026 Ortona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Saveria","family":"Tavoletta","sequence":"additional","affiliation":[{"name":"Breast Unit, P.O. \u201cG. Bernabeo\u201d, 66026 Ortona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Grossi","sequence":"additional","affiliation":[{"name":"Breast Unit, P.O. \u201cG. Bernabeo\u201d, 66026 Ortona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7317-3733","authenticated-orcid":false,"given":"Alessandra","family":"Babore","sequence":"additional","affiliation":[{"name":"Department of Psychological, Health and Territory Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Milillo","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Innovative Technologies in Medicine and Dentistry, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melania","family":"Dovizio","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Innovative Technologies in Medicine and Dentistry, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Ballerini","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Innovative Technologies in Medicine and Dentistry, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9999-5823","authenticated-orcid":false,"given":"Valentina","family":"Gatta","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Neurosciences, Imaging and Clinical Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6232-0996","authenticated-orcid":false,"given":"Liborio","family":"Stuppia","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Neurosciences, Imaging and Clinical Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6594-2272","authenticated-orcid":false,"given":"Ivana","family":"Antonucci","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Neurosciences, Imaging and Clinical Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Mutation detection in patients with advanced cancer by universal sequencing","volume":"8","author":"Mandelker","year":"2022","journal-title":"JAMA Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41389-022-00393-8","article-title":"Breast cancer in the era of integrating \u201cOmics\u201d approaches","volume":"11","author":"Rossi","year":"2022","journal-title":"Oncogenesis"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Anaclerio, F., Pilenzi, L., Dell\u2019Elice, A., Ferrante, R., Grossi, S., Ferlito, L.M., Marinelli, C., Gildetti, S., Calabrese, G., and Stuppia, L. 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