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High-penetrance genes (BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, TP53) inform specific clinical surveillance and therapeutic decisions, while recommendations for moderate-penetrance genes (ATM, BARD1, BRIP1, CHEK2, MLH1, MSH2, MSH6, PMS2, EPCAM, NF1, RAD51C, RAD51D) are more limited. A detailed disease history, including pedigree data, helps formulate the most appropriate and personalised management strategies. In this study, we evaluated the clinical benefits of comprehensive hereditary cancer gene panel testing and a pre-sent questionnaire in Hungarian patients with suspected HBOC syndrome. We prospectively enrolled 513 patients referred for HBOC testing. Of these, 463 met the genetic testing criteria, while 50 did not but were tested due to potential therapeutic indications. Additionally, a retrospective cohort of 47 patients who met the testing criteria but had previously only been tested for BRCA1\/2 was also analysed. Among the 463 patients in the prospective cohort, 96 (20.7%) harboured pathogenic\/likely pathogenic (P\/LP) variants\u201467 in high-penetrance genes and 29 in moderate-penetrance genes. This ratio was similar in the retrospective cohort (6\/47; 12.7%). In patients who did not meet the testing criteria, no mutations in high-penetrance genes were found, and only 3 of 50 (6%) harboured P\/LP variants in moderate-penetrance genes. Secondary findings (P\/LP variants in non-HBOC-associated genes) were identified in two patients. In the prospective cohort, P\/LP variants in BRCA1 and BRCA2 were the most prevalent (56\/96; 58.3%), and the extended testing doubled the P\/LP detection ratio. Among moderate-penetrance genes, five cases (three in the prospective and two in the retrospective cohorts) had P\/LP variants in Lynch syndrome-associated genes. Further immunohistochemistry analysis of breast tumour tissues helped clarify the causative role of these variants. Comprehensive clinical and molecular genetic evaluation is beneficial for the diagnosis and management of patients with P\/LP variants in hereditary tumour-predisposing genes and can serve as a basis for effective therapy selection, such as PARP inhibitors or immunotherapy.<\/jats:p>","DOI":"10.3390\/ijms252312546","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T06:41:48Z","timestamp":1732257708000},"page":"12546","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Comprehensive Clinical Genetics, Molecular and Pathological Evaluation Efficiently Assist Diagnostics and Therapy Selection in Breast Cancer Patients with Hereditary Genetic Background"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4336-8444","authenticated-orcid":false,"given":"Petra","family":"Nagy","sequence":"first","affiliation":[{"name":"Department of Molecular 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Hereditary Tumours Research Group, Hungarian Research Network, Nagyv\u00e1rad t\u00e9r 4, 1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5410-9173","authenticated-orcid":false,"given":"Anik\u00f3","family":"Bozsik","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and The National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Centre, R\u00e1th Gy\u00f6rgy u. 7-9, 1122 Budapest, Hungary"},{"name":"HUN-REN-SE Hereditary Tumours Research Group, Hungarian Research Network, Nagyv\u00e1rad t\u00e9r 4, 1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T\u00edmea","family":"P\u00f3cza","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and The National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Centre, R\u00e1th Gy\u00f6rgy u. 7-9, 1122 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edit","family":"Ol\u00e1h","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and The National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Centre, R\u00e1th Gy\u00f6rgy u. 7-9, 1122 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7506-674X","authenticated-orcid":false,"given":"Attila","family":"Pat\u00f3cs","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and The National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Centre, R\u00e1th Gy\u00f6rgy u. 7-9, 1122 Budapest, Hungary"},{"name":"HUN-REN-SE Hereditary Tumours Research Group, Hungarian Research Network, Nagyv\u00e1rad t\u00e9r 4, 1089 Budapest, Hungary"},{"name":"Department of Laboratory Medicine, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, 1089 Budapest, 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