{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:12:58Z","timestamp":1783642378796,"version":"3.55.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":64,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-026-50634-8","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T10:53:54Z","timestamp":1778151234000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Whole exome sequencing reveals rare DNA repair gene variants in BRCA1\/2-negative Arab early-onset breast cancer patients"],"prefix":"10.1038","volume":"16","author":[{"given":"Rong","family":"Bu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul K.","family":"Siraj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman A.","family":"Abdul Razzaq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaleem","family":"Iqbal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep Kumar","family":"Parvathareddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saud","family":"Azam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeeshan","family":"Qadri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saravanan","family":"Thangavel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wael","family":"Haqawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4126-3419","authenticated-orcid":false,"given":"Khawla S.","family":"Al-Kuraya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"issue":"3","key":"50634_CR1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray, F. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 74(3), 229\u2013263. https:\/\/doi.org\/10.3322\/caac.21834 (2024).","journal-title":"CA Cancer J. Clin."},{"issue":"1","key":"50634_CR2","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3322\/caac.21820","volume":"74","author":"RL Siegel","year":"2024","unstructured":"Siegel, R. L., Giaquinto, A. N. & Jemal, A. Cancer statistics, 2024. CA Cancer J. Clin. 74(1), 12\u201349. https:\/\/doi.org\/10.3322\/caac.21820 (2024).","journal-title":"CA Cancer J. Clin."},{"key":"50634_CR3","unstructured":"Saudi Health, C. Saudi Cancer Registry Annual Reports (2022)."},{"issue":"11","key":"50634_CR4","doi-asserted-by":"publisher","first-page":"1617","DOI":"10.3390\/medicina58111617","volume":"58","author":"AM Basudan","year":"2022","unstructured":"Basudan, A. M. Breast cancer incidence patterns in the Saudi female population: A 17-year retrospective analysis. Medicina 58(11), 1617 (2022).","journal-title":"Medicina"},{"issue":"1","key":"50634_CR5","doi-asserted-by":"publisher","first-page":"370385","DOI":"10.1155\/2012\/370385","volume":"2012","author":"V Rudat","year":"2012","unstructured":"Rudat, V. et al. Age of 40 years or younger is an independent risk factor for locoregional failure in early breast cancer: A single-institutional analysis in saudi arabia. J. Oncol. 2012(1), 370385. https:\/\/doi.org\/10.1155\/2012\/370385 (2012).","journal-title":"J. Oncol."},{"issue":"1","key":"50634_CR6","doi-asserted-by":"publisher","first-page":"20816","DOI":"10.1038\/s41598-025-05276-7","volume":"15","author":"H Almohanna","year":"2025","unstructured":"Almohanna, H. et al. A comprehensive epidemiological analysis of breast cancer in the Eastern Province of Saudi Arabia. Sci. Rep. 15(1), 20816. https:\/\/doi.org\/10.1038\/s41598-025-05276-7 (2025).","journal-title":"Sci. Rep."},{"issue":"3","key":"50634_CR7","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.jamcollsurg.2008.12.001","volume":"208","author":"JL Gnerlich","year":"2009","unstructured":"Gnerlich, J. L. et al. Elevated breast cancer mortality in women younger than age 40 years compared with older women is attributed to poorer survival in early-stage disease. J. Am. Coll. Surg. 208(3), 341\u2013347 (2009).","journal-title":"J. Am. Coll. Surg."},{"key":"50634_CR8","doi-asserted-by":"crossref","unstructured":"Anders, C. K., Johnson, R., Litton, J., Phillips, M. & Bleyer, A. Breast Cancer Before age 40 Years 237\u2013249 (Elsevier, 2009).","DOI":"10.1053\/j.seminoncol.2009.03.001"},{"issue":"1","key":"50634_CR9","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s12905-022-02142-w","volume":"23","author":"PK Akakpo","year":"2023","unstructured":"Akakpo, P. K. et al. Clinicopathologic characteristics of early-onset breast cancer: A comparative analysis of cases from across Ghana. BMC Womens Health 23(1), 5. https:\/\/doi.org\/10.1186\/s12905-022-02142-w (2023).","journal-title":"BMC Womens Health"},{"issue":"3","key":"50634_CR10","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.jamcollsurg.2008.12.001","volume":"208","author":"JL Gnerlich","year":"2009","unstructured":"Gnerlich, J. L. et al. Elevated breast cancer mortality in women younger than age 40 years compared with older women is attributed to poorer survival in early-stage disease. J. Am. Coll. Surg. 208(3), 341\u2013347. https:\/\/doi.org\/10.1016\/j.jamcollsurg.2008.12.001 (2009).","journal-title":"J. Am. Coll. Surg."},{"issue":"1","key":"50634_CR11","doi-asserted-by":"publisher","first-page":"17573","DOI":"10.1038\/s41598-020-74250-2","volume":"10","author":"M Abu-Helalah","year":"2020","unstructured":"Abu-Helalah, M. et al. BRCA1 and BRCA2 genes mutations among high risk breast cancer patients in Jordan. Sci. Rep. 10(1), 17573. https:\/\/doi.org\/10.1038\/s41598-020-74250-2 (2020).","journal-title":"Sci. Rep."},{"key":"50634_CR12","doi-asserted-by":"crossref","unstructured":"Criscitiello, C. & Corti, C. Breast Cancer Genetics: Diagnostics and Treatment 1593 (MDPI, 2022).","DOI":"10.3390\/genes13091593"},{"issue":"5","key":"50634_CR13","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1002\/ijc.30143","volume":"139","author":"R Bu","year":"2016","unstructured":"Bu, R. et al. Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis. Int. J. Cancer 139(5), 1091\u20131097. https:\/\/doi.org\/10.1002\/ijc.30143 (2016).","journal-title":"Int. J. Cancer"},{"key":"50634_CR14","doi-asserted-by":"crossref","unstructured":"Bu, R. et al. Identification and characterization of ATM founder mutation in BRCA-negative breast cancer patients of Arab ethnicity. Sci. Rep. 13(1), 20924 (2023).","DOI":"10.1038\/s41598-023-48231-0"},{"key":"50634_CR15","doi-asserted-by":"publisher","unstructured":"Rahman, S. & Zayed, H. Breast cancer in the GCC countries: A focus on BRCA1\/2 and non-BRCA1\/2 genes. Gene 668, 73\u201376. https:\/\/doi.org\/10.1016\/j.gene.2018.05.045 (2018).","DOI":"10.1016\/j.gene.2018.05.045"},{"key":"50634_CR16","doi-asserted-by":"publisher","first-page":"153303382513368","DOI":"10.1177\/15330338251336829","volume":"24","author":"WS Al Amri","year":"2025","unstructured":"Al Amri, W. S., Al Jabri, M., Al Abri, A. & Hughes, T. A. Cancer genetics in the Arab world. Technol. Cancer Res. Treat. 24, 15330338251336829. https:\/\/doi.org\/10.1177\/15330338251336829 (2025).","journal-title":"Technol. Cancer Res. Treat."},{"issue":"9","key":"50634_CR17","doi-asserted-by":"publisher","first-page":"3003","DOI":"10.3390\/jcm9093003","volume":"9","author":"A Germani","year":"2020","unstructured":"Germani, A. et al. Beyond BRCA1 and BRCA2: Deleterious variants in DNA repair pathway genes in italian families with breast\/ovarian and pancreatic cancers. J. Clin. Med. 9(9), 3003. https:\/\/doi.org\/10.3390\/jcm9093003 (2020).","journal-title":"J. Clin. Med."},{"key":"50634_CR18","doi-asserted-by":"publisher","first-page":"674094","DOI":"10.3389\/fgene.2021.674094","volume":"12","author":"Y Su","year":"2021","unstructured":"Su, Y. et al. Characteristics of germline Non-BRCA mutation status of high-risk breast cancer patients in China and correlation with high-risk factors and multigene testing suggestions. Front. Genet. 12, 674094. https:\/\/doi.org\/10.3389\/fgene.2021.674094 (2021).","journal-title":"Front. Genet."},{"issue":"17","key":"50634_CR19","doi-asserted-by":"publisher","first-page":"2955","DOI":"10.3390\/cancers16172955","volume":"16","author":"V Kurkilahti","year":"2024","unstructured":"Kurkilahti, V. et al. Rare germline variants in DNA repair genes detected in BRCA-negative Finnish patients with early-onset breast cancer. Cancers 16(17), 2955. https:\/\/doi.org\/10.3390\/cancers16172955 (2024).","journal-title":"Cancers (Basel)"},{"issue":"1","key":"50634_CR20","doi-asserted-by":"publisher","first-page":"20924","DOI":"10.1038\/s41598-023-48231-0","volume":"13","author":"R Bu","year":"2023","unstructured":"Bu, R. et al. Identification and characterization of ATM founder mutation in BRCA-negative breast cancer patients of Arab ethnicity. Sci. Rep. 13(1), 20924. https:\/\/doi.org\/10.1038\/s41598-023-48231-0 (2023).","journal-title":"Sci. Rep."},{"issue":"8","key":"50634_CR21","doi-asserted-by":"publisher","first-page":"1962","DOI":"10.1002\/ijc.31921","volume":"144","author":"E Girard","year":"2019","unstructured":"Girard, E. et al. Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. Int. J. Cancer 144(8), 1962\u20131974. https:\/\/doi.org\/10.1002\/ijc.31921 (2019).","journal-title":"Int. J. Cancer"},{"key":"50634_CR22","doi-asserted-by":"publisher","unstructured":"Wood, R. D., Mitchell, M. & Lindahl, T. Human DNA repair genes, 2005. Mutat. Res. 577(1\u20132), 275\u2013283. https:\/\/doi.org\/10.1016\/j.mrfmmm.2005.03.007 (2005).","DOI":"10.1016\/j.mrfmmm.2005.03.007"},{"issue":"4","key":"50634_CR23","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","volume":"99","author":"NM Ioannidis","year":"2016","unstructured":"Ioannidis, N. M. et al. REVEL: An ensemble method for predicting the pathogenicity of rare missense variants. Am. J. Hum. Genet. 99(4), 877\u2013885. https:\/\/doi.org\/10.1016\/j.ajhg.2016.08.016 (2016).","journal-title":"Am. J. Hum. Genet."},{"issue":"3","key":"50634_CR24","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","volume":"176","author":"K Jaganathan","year":"2019","unstructured":"Jaganathan, K. et al. Predicting splicing from primary sequence with deep learning. Cell 176(3), 535\u2013548 (2019).","journal-title":"Cell"},{"issue":"13","key":"50634_CR25","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1002\/jcc.20084","volume":"25","author":"EF Pettersen","year":"2004","unstructured":"Pettersen, E. F. et al. UCSF Chimera\u2013a visualization system for exploratory research and analysis. J. Comput. Chem. 25(13), 1605\u20131612. https:\/\/doi.org\/10.1002\/jcc.20084 (2004).","journal-title":"J. Comput. Chem."},{"key":"50634_CR26","doi-asserted-by":"publisher","unstructured":"Pires, D. E., Ascher, D. B. & Blundell, T. L. DUET: A server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res. 42, W314\u2013W319. https:\/\/doi.org\/10.1093\/nar\/gku411 (2014).","DOI":"10.1093\/nar\/gku411"},{"key":"50634_CR27","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.dnarep.2017.09.001","volume":"59","author":"PP Jia","year":"2017","unstructured":"Jia, P. P. et al. Role of human DNA2 (hDNA2) as a potential target for cancer and other diseases: A systematic review. DNA Repair. 59, 9\u201319. https:\/\/doi.org\/10.1016\/j.dnarep.2017.09.001 (2017).","journal-title":"DNA Repair. (Amst)"},{"issue":"1","key":"50634_CR28","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1093\/nar\/gkz1101","volume":"48","author":"L Zheng","year":"2020","unstructured":"Zheng, L., Meng, Y., Campbell, J. L. & Shen, B. Multiple roles of DNA2 nuclease\/helicase in DNA metabolism, genome stability and human diseases. Nucleic Acids Res. 48(1), 16\u201335. https:\/\/doi.org\/10.1093\/nar\/gkz1101 (2020).","journal-title":"Nucleic Acids Res."},{"issue":"18","key":"50634_CR29","doi-asserted-by":"publisher","first-page":"26793","DOI":"10.18632\/oncotarget.8471","volume":"7","author":"SY Park","year":"2016","unstructured":"Park, S. Y., Piao, Y., Thomas, C., Fuller, G. N. & De Groot, J. F. Cdc2-like kinase 2 is a key regulator of the cell cycle via FOXO3a\/p27 in glioblastoma. Oncotarget 7(18), 26793 (2016).","journal-title":"Oncotarget"},{"issue":"10","key":"50634_CR30","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1016\/j.chembiol.2023.06.027","volume":"30","author":"P Mucka","year":"2023","unstructured":"Mucka, P. et al. CLK2 and CLK4 are regulators of DNA damage-induced NF-\u03baB targeted by novel small molecule inhibitors. Cell. Chem. Biol. 30(10), 1303\u20131312 (2023)","journal-title":"Cell. Chem. Biology"},{"issue":"6","key":"50634_CR31","doi-asserted-by":"publisher","first-page":"3833","DOI":"10.1093\/nar\/gkt1333","volume":"42","author":"A Pepe","year":"2014","unstructured":"Pepe, A. & West, S. C. Substrate specificity of the MUS81-EME2 structure selective endonuclease. Nucleic Acids Res. 42(6), 3833\u20133845 (2014).","journal-title":"Nucleic Acids Res."},{"issue":"9","key":"50634_CR32","doi-asserted-by":"publisher","first-page":"5846","DOI":"10.1093\/nar\/gku237","volume":"42","author":"T Amangyeld","year":"2014","unstructured":"Amangyeld, T., Shin, Y-K., Lee, M., Kwon, B. & Seo, Y-S. Human MUS81-EME2 can cleave a variety of DNA structures including intact Holliday junction and nicked duplex. Nucleic Acids Res. 42(9), 5846\u20135862 (2014).","journal-title":"Nucleic Acids Res."},{"issue":"10","key":"50634_CR33","doi-asserted-by":"publisher","first-page":"e1001160","DOI":"10.1371\/journal.pgen.1001160","volume":"6","author":"Y Akamatsu","year":"2010","unstructured":"Akamatsu, Y. & Jasin, M. Role for the mammalian Swi5-Sfr1 complex in DNA strand break repair through homologous recombination. PLoS Genet. 6(10), e1001160 (2010).","journal-title":"PLoS Genet."},{"issue":"13","key":"50634_CR34","doi-asserted-by":"publisher","first-page":"6242","DOI":"10.1093\/nar\/gkw375","volume":"44","author":"G-C Su","year":"2016","unstructured":"Su, G-C. et al. Role of the RAD51\u2013SWI5\u2013SFR1 ensemble in homologous recombination. Nucleic Acids Res. 44(13), 6242\u20136251 (2016).","journal-title":"Nucleic Acids Res."},{"issue":"1","key":"50634_CR35","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1038\/s41523-021-00339-0","volume":"7","author":"J Setton","year":"2021","unstructured":"Setton, J. et al. Germline RAD51B variants confer susceptibility to breast and ovarian cancers deficient in homologous recombination. NPJ Breast Cancer 7(1), 135 (2021).","journal-title":"NPJ breast cancer"},{"issue":"04","key":"50634_CR36","doi-asserted-by":"publisher","first-page":"192","DOI":"10.3934\/genet.2018.4.192","volume":"5","author":"MY Son","year":"2018","unstructured":"Son, M. Y. & Hasty, P. Homologous recombination defects and how they affect replication fork maintenance. AIMS Genet. 5(04), 192\u2013211 (2018).","journal-title":"AIMS Genet."},{"issue":"1","key":"50634_CR37","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/s41698-023-00354-3","volume":"7","author":"M Esai Selvan","year":"2023","unstructured":"Esai Selvan, M., Onel, K., Gnjatic, S., Klein, R. J. & G\u00fcm\u00fc\u015f, Z. H. Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics. NPJ Precis. Oncol. 7(1), 13 (2023).","journal-title":"NPJ Precision Oncol."},{"issue":"7","key":"50634_CR38","doi-asserted-by":"publisher","first-page":"e208501","DOI":"10.1001\/jamanetworkopen.2020.8501","volume":"3","author":"S Gallagher","year":"2020","unstructured":"Gallagher, S. et al. Association of a polygenic risk score with breast cancer among women carriers of high-and moderate-risk breast cancer genes. JAMA Netw. Open 3(7), e208501 (2020).","journal-title":"JAMA Netw. open."},{"key":"50634_CR39","unstructured":"Schr\u00f6dinger, L. & DeLano, W. PyMOL (2020)."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-50634-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-50634-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-50634-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T23:14:17Z","timestamp":1783638857000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-50634-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,7]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["50634"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-50634-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,7]]},"assertion":[{"value":"13 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Approved by the Institutional Review Board of King Faisal Specialist Hospital & Research Center (RAC number 2140 008.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Since the study was conducted on retrospective specimens, a waiver of informed consent has been obtained from Institutional Review Board of King Faisal Specialist Hospital & Research Center (RAC#2140 008).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}}],"article-number":"21490"}}