{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:23:01Z","timestamp":1788456181968,"version":"build-2803163510"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p><jats:italic>BRCA1<\/jats:italic> and <jats:italic>BRCA2<\/jats:italic> genes are well-established tumor suppressors, crucial for maintaining genomic stability through their roles in DNA repair. Pathogenic variants in <jats:italic>BRCA1\/2<\/jats:italic> genes are implicated in increased susceptibility to breast and ovarian cancers. However, variant interpretation remains challenging due to the large size of <jats:italic>BRCA1\/2<\/jats:italic> (&amp;gt;80 kb) and the broad spectrum of variant forms, particularly for rare or recently identified variants lacking adequate population, functional or segregation data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Case presentation<\/jats:title><jats:p>This report describes a case of high-grade serous ovarian carcinoma in a patient with a strong family history of cancer. Both her mother and sister died of ovarian cancer. Genetic testing identified the germline variant <jats:italic>BRCA1 c.5193 + 2dupT<\/jats:italic> both in the patient\u2019s tumor and peripheral blood samples, without other abnormalities detected in genomic homologous recombination deficiency assessment. Her daughter was identified as an unaffected carrier of this variant. Unfortunately, the <jats:italic>BRCA1<\/jats:italic> status of deceased relatives could not be determined due to the unavailability of samples. Functional studies, including minigene splicing assay and transcript analysis, demonstrated that this variant induces a splicing error, specifically, an aberrant skipping of exon 18, resulting in dysfunction of the <jats:italic>BRCA1<\/jats:italic>-encoded protein. These findings provide a mechanistic explanation for the observed cancer susceptibility in this family.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This case highlights a rare germline variant, <jats:italic>BRCA1 c.5193 + 2dupT<\/jats:italic>, in a family with a strong cancer history. <jats:italic>In vitro<\/jats:italic> functional assays confirmed that this variant induces exon 18 skipping through aberrant splicing, leading to dysfunction of <jats:italic>BRCA1<\/jats:italic>-encoded protein. To our knowledge, this is the first functional characterization of the variant <jats:italic>BRCA1 c.5193 + 2dupT<\/jats:italic>, and our data provide novel insights for risk assessment and precision treatment strategies in carriers of this variant.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2025.1623700","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T04:11:23Z","timestamp":1759205483000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Case Report: Functional validation of a rare variant BRCA1 c.5193 + 2dupT in a family with cancer history"],"prefix":"10.3389","volume":"15","author":[{"given":"Guanlin","family":"Dai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danqing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2024.102713","article-title":"Global, regional, and national burden of. female cancers in women of child-bearing age, 1990\u20132021: analysis of data from the global burden of disease study 2021","volume":"74","author":"Sun","year":"2024","journal-title":"eClinicalMedicine"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3934","article-title":"A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer","volume":"49","author":"Polak","year":"2017","journal-title":"Nat Genet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2402","DOI":"10.1001\/jama.2017.7112","article-title":"Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers","volume":"317","author":"Kuchenbaecker","year":"2017","journal-title":"JAMA"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1415979111","article-title":"Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2","volume":"111","author":"Gabai-Kapara","year":"2014","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2015.181","article-title":"Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations","volume":"35","author":"Golmard","year":"2016","journal-title":"Oncogene"},{"key":"B6","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1002\/ijc.32396","article-title":"Breast cancer risk in BRCA1\/2 mutation carriers and noncarriers under prospective intensified surveillance","volume":"146","author":"Engel","year":"2020","journal-title":"Int J Cancer"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2023.06.002","article-title":"Using the ACMG\/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup","volume":"110","author":"Walker","year":"2023","journal-title":"Am J Hum Gene"},{"key":"B8","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s13073-019-0688-9","article-title":"Is \u201clikely pathogenic\u201d really 90% likely? 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