{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T11:55:29Z","timestamp":1769255729102,"version":"3.49.0"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Regional Government of Castile and Leon to the University of Valladolid, Valladolid (Spain)","award":["GRS\/2351\/A\/2021"],"award-info":[{"award-number":["GRS\/2351\/A\/2021"]}]},{"name":"Regional Government of Castile and Leon to the University of Valladolid, Valladolid (Spain)","award":["EDU\/842\/2022"],"award-info":[{"award-number":["EDU\/842\/2022"]}]},{"name":"European Social Fund Plus and the Operational Programme of the Regional Government of Castilla y Le\u00f3n","award":["GRS\/2351\/A\/2021"],"award-info":[{"award-number":["GRS\/2351\/A\/2021"]}]},{"name":"European Social Fund Plus and the Operational Programme of the Regional Government of Castilla y Le\u00f3n","award":["EDU\/842\/2022"],"award-info":[{"award-number":["EDU\/842\/2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background and Objectives: Despite the well-established role of the BRCA and mismatch repair (MMR) genes in DNA damage repair pathways, a substantial proportion of familial cancer cases still lack pathogenic variants in those genes. Next Generation Sequencing (NGS) panels have emerged as a powerful tool to identify hereditary cancer at-risk individuals and subsequently provide them with accurate management. Materials and Methods: Families harbouring PVs in RAD50, RAD51C, RAD51D, and BRIP1 were identified by analysing a cancer-predisposing genes panel using Ion S5 system technology. A retrospective cohort of 155 families tested only for the BRCAs of MMR genes were reanalysed, prompted by an increase in familial cases or new cancer diagnoses among index cases. Results: We identified 40 families through molecular reanalysis (33 with Hereditary Breast and Ovarian Cancer (HBOC) and 7 with Lynch Syndrome (LS)), with positive test results among 155 families lacking BRCA or MMR mutations. The most frequently mutated genes after ATM and CHEK2 were BRIP1, RAD51D, and RAD51C with 16, 13, and 9 positive families, respectively. The phenotype\u2013genotype correlations not only revealed ovarian and HER-negative breast cancer predispositions but also other cancer types, particularly lung and gastric, and individuals with a second or third distinct cancer episode. Conclusions: Broader ranges of malignancies, including gastric, lung, and bladder, have been identified among BRIP1, RAD51D, and RAD51C positive families. The results generated using NGS provide a comprehensive genetic landscape in each patient that could explain the diversity of phenotypes shown in PV families that, combined with non-genetic factors, might enable accurate surveillance and personalized treatments. NGS reanalysis doubled our diagnostic yield and was a good strategy to identify hereditary cancer families that would otherwise be overlooked.<\/jats:p>","DOI":"10.3390\/genes16040458","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T10:04:56Z","timestamp":1744797896000},"page":"458","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Genetic Features of Tumours Arising in the Context of Suspected Hereditary Cancer Syndromes with RAD50, RAD51C\/D, and BRIP1 Germline Mutations, Results of NGS-Reanalysis of BRCA\/MMR-Negative Families"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1707-4001","authenticated-orcid":false,"given":"M\u00f3nica","family":"Arranz-Ledo","sequence":"first","affiliation":[{"name":"Cancer Genetics Group, Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid-Spanish National Research Council (UVa-CSIC), C\/Sanz y For\u00e9s 3, 47003 Valladolid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7197-5249","authenticated-orcid":false,"given":"Mar","family":"Infante","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid-Spanish National Research Council (UVa-CSIC), C\/Sanz y For\u00e9s 3, 47003 Valladolid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrique","family":"Lastra","sequence":"additional","affiliation":[{"name":"Unit of Genetic Counseling in Cancer, Complejo Hospitalario de Burgos, 09006 Burgos, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amaya","family":"Olaverri","sequence":"additional","affiliation":[{"name":"Unit of Genetic Counseling in Cancer, Hospital Universitario Rio Hortega, 47012 Valladolid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Orozco","sequence":"additional","affiliation":[{"name":"Unit of Genetic Counseling in Cancer, Hospital Universitario Rio Hortega, 47012 Valladolid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4273-1967","authenticated-orcid":false,"given":"Lucia C.","family":"Mateo","sequence":"additional","affiliation":[{"name":"Unit of Genetic Counseling in Cancer, Hospital Universitario Rio Hortega, 47012 Valladolid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noem\u00ed","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid-Spanish National Research Council (UVa-CSIC), C\/Sanz y For\u00e9s 3, 47003 Valladolid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lara","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid-Spanish National Research Council (UVa-CSIC), C\/Sanz y For\u00e9s 3, 47003 Valladolid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mercedes","family":"Dur\u00e1n","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid-Spanish National Research Council (UVa-CSIC), C\/Sanz y For\u00e9s 3, 47003 Valladolid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1200\/JCO.21.02112","article-title":"Cancer Risks Associated with BRCA1 and BRCA2 Pathogenic Variants","volume":"40","author":"Li","year":"2022","journal-title":"J. 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