{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T11:47:31Z","timestamp":1764762451260,"version":"3.46.0"},"reference-count":30,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research, Development and Innovation Fund of the Ministry of Culture and Innovation","award":["2022-2.1.1-NL-2022-00010"],"award-info":[{"award-number":["2022-2.1.1-NL-2022-00010"]}]},{"name":"Hungarian Thematic Excellence Program","award":["TKP2021-EGA-44"],"award-info":[{"award-number":["TKP2021-EGA-44"]}]},{"name":"J\u00e1nos Bolyai Postdoctoral Scholarship","award":["BO\/00141\/21"],"award-info":[{"award-number":["BO\/00141\/21"]}]},{"name":"New National Excellence Program Bolyai+ Scholarship","award":["\u00daNKP-23-5-SE-16"],"award-info":[{"award-number":["\u00daNKP-23-5-SE-16"]}]},{"name":"COST Action CA20122 Harmonization"},{"name":"NRDI","award":["NKFI-FK135065"],"award-info":[{"award-number":["NKFI-FK135065"]}]},{"name":"New National Excellence Program of the Ministry of Human Capacities","award":["\u00daNKP-23-5-SE-4"],"award-info":[{"award-number":["\u00daNKP-23-5-SE-4"]}]},{"name":"Bolyai Research Fellowship of the Hungarian Academy of Sciences"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Germline BRCA1 mutations account for ~15\u201320% of hereditary breast and ovarian cancer (HBOC) cases. While most are small sequence variants, structural rearrangements also contribute significantly to the pathogenic landscape. Conventional diagnostic workflows often miss such events, underscoring the need for comprehensive approaches. Here, we report a previously undescribed pathogenic mechanism\u2014a transposon-mediated processed transcript insertion\u2014expanding the mutational spectrum underlying hereditary breast cancer susceptibility. Methods: The studied case was discovered during our germline genotyping routine: next-generation sequencing followed by library preparation with a custom hereditary cancer panel. The identified variant was validated by orthogonal sequencing and multiplex ligation-dependent probe amplification (MLPA). RNA-level functional assays, including nonsense-mediated decay inhibition, were conducted to assess transcript stability. Constitutional origin was confirmed by analysis of multiple normal tissues, and tumor material was evaluated for loss of heterozygosity (LOH). Results: NGS detected a 700 bp insertion in exon 16 of BRCA1, corresponding to a complete processed transcript of RPL18A. The insertion caused a frameshift and premature stop codon, triggering degradation of the aberrant transcript. The variant was present in multiple somatic tissues, and its heritable nature was further confirmed by genotyping a first-degree relative, who was also found to carry the insertion. Tumor DNA analysis revealed strong LOH with retention of the variant allele. Conclusions: This study identifies, for the first time, a heritable processed transcript insertion as a pathogenic event in BRCA1. Such variants are undetectable by conventional diagnostic workflows lacking structural variant analysis, highlighting the importance of comprehensive approaches for accurate diagnosis and genetic counselling in hereditary cancer syndromes.<\/jats:p>","DOI":"10.3390\/cancers17233872","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T11:29:30Z","timestamp":1764761370000},"page":"3872","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Processed Transcript Insertion as a Novel Germline Mutational Mechanism in BRCA1-Associated Hereditary Breast Cancer"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5410-9173","authenticated-orcid":false,"given":"Anik\u00f3","family":"Bozsik","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Center, 1122 Budapest, Hungary"},{"name":"HUN-REN-OOI-TTK-HCEMM Oncogenomics Research Group, 1054 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1664-409X","authenticated-orcid":false,"given":"Henriett","family":"Butz","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Center, 1122 Budapest, Hungary"},{"name":"HUN-REN-OOI-TTK-HCEMM Oncogenomics Research Group, 1054 Budapest, Hungary"},{"name":"Department of Laboratory Medicine, Semmelweis University, 1122 Budapest, Hungary"},{"name":"Department of Oncology Biobank, National Institute of Oncology, 1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vince Korn\u00e9l","family":"Grolmusz","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Center, 1122 Budapest, Hungary"},{"name":"HUN-REN-OOI-TTK-HCEMM Oncogenomics Research Group, 1054 Budapest, Hungary"},{"name":"MTA-OOI Lend\u00fclet \u201cMomentum\u201d Hereditary Cancers Systems Biology Research Group, 1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4336-8444","authenticated-orcid":false,"given":"Petra","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Center, 1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T\u00edmea","family":"P\u00f3cza","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Center, 1122 Budapest, Hungary"},{"name":"HUN-REN-OOI-TTK-HCEMM Oncogenomics Research Group, 1054 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2054-8447","authenticated-orcid":false,"given":"Erika","family":"T\u00f3th","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, National Institute of Oncology, Comprehensive Cancer Center, 1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erzs\u00e9bet","family":"Csern\u00e1k","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, National Institute of Oncology, Comprehensive Cancer Center, 1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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 National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Center, 1122 Budapest, Hungary"},{"name":"HUN-REN-OOI-TTK-HCEMM Oncogenomics Research Group, 1054 Budapest, Hungary"},{"name":"Department of Laboratory Medicine, Semmelweis University, 1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00e1nos","family":"Papp","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Center, 1122 Budapest, Hungary"},{"name":"HUN-REN-OOI-TTK-HCEMM Oncogenomics Research Group, 1054 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"77","DOI":"10.6004\/jnccn.2021.0001","article-title":"Genetic\/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in 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