{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:33:43Z","timestamp":1785407623685,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["101079217"],"award-info":[{"award-number":["101079217"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"award":["101079217"],"award-info":[{"award-number":["101079217"]}],"id":[{"id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by germline pathogenic or likely pathogenic variants (PV\/LPV) in mismatch repair (MMR) genes. Data on the spectrum of LS-associated variants in Slavic populations, including Serbia, remain limited. Given the high burden of CRC and endometrial cancer and the limited implementation of hereditary CRC screening, characterizing the spectrum of germline variants in clinically selected high-risk individuals is important for improving genetic testing strategies, risk assessment, and clinical management. Between 2018 and 2025, 176 individuals underwent germline testing for hereditary CRC syndrome based on the Amsterdam\/Bethesda criteria, validated LS risk prediction models, and\/or family history (FH). Next-generation sequencing (NGS) was performed using the Illumina TruSight Hereditary Cancer Panel, and variants were classified according to American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG\/AMP) guidelines. PV\/LPVs in MMR genes were identified in 27\/176 (15.3%) and were associated with positive FH of LS-related tumors (p = 0.0001). Most PV\/LPVs were identified in MLH1 (10.2%), followed by MSH2 (4.0%) and MSH6 (1.1%), with no PV\/LPVs identified in PMS2. Additionally, no pathogenic sequence-level EPCAM variants detectable by the applied panel-based NGS approach were identified. Recurrent MLH1 variants were observed in multiple families, and two previously unreported MLH1 variants were identified. This first systematic analysis of a clinically selected high-risk Serbian cohort provides novel data on the spectrum of LS-associated variants in this referral population, demonstrates the predominance of MLH1 variants, and supports broader implementation of genetic testing, tumor screening, and genetic counseling.<\/jats:p>","DOI":"10.3390\/ijms27156652","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:47:41Z","timestamp":1785145661000},"page":"6652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Landscape of Lynch Syndrome in a High-Risk Serbian Cohort: Predominance of MLH1 Variants and Implications for Risk-Based Testing"],"prefix":"10.3390","volume":"27","author":[{"given":"Marija","family":"Djordjic Crnogorac","sequence":"first","affiliation":[{"name":"Department for Genetic Counseling for Hereditary Cancer, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0888-5719","authenticated-orcid":false,"given":"Valentina","family":"Karadzic","sequence":"additional","affiliation":[{"name":"Department for Genetic Counseling for Hereditary Cancer, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodora","family":"Cato","sequence":"additional","affiliation":[{"name":"Department for Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7604-9295","authenticated-orcid":false,"given":"Milena","family":"Cavic","sequence":"additional","affiliation":[{"name":"Department for Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0571-2272","authenticated-orcid":false,"given":"Neda","family":"Nikolic","sequence":"additional","affiliation":[{"name":"Clinic for Medical Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1386-9114","authenticated-orcid":false,"given":"Jelena","family":"Spasic","sequence":"additional","affiliation":[{"name":"Clinic for Medical Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4003-399X","authenticated-orcid":false,"given":"Fedja","family":"Djordjevic","sequence":"additional","affiliation":[{"name":"Clinic for Medical Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2737-3670","authenticated-orcid":false,"given":"Vladimir","family":"Jokic","sequence":"additional","affiliation":[{"name":"Clinic for Surgical Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2977-3173","authenticated-orcid":false,"given":"Milan","family":"Kocic","sequence":"additional","affiliation":[{"name":"Clinic for Surgical Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miroslav","family":"Djurasinovic","sequence":"additional","affiliation":[{"name":"Clinic for Medical Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biljana","family":"Kukic","sequence":"additional","affiliation":[{"name":"Department for Medical Oncology, Oncology Institute of Vojvodina, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7027-9834","authenticated-orcid":false,"given":"Srdjan","family":"Nikolic","sequence":"additional","affiliation":[{"name":"Clinic for Surgical Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Ristic","sequence":"additional","affiliation":[{"name":"Clinic for Medical Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1371-1918","authenticated-orcid":false,"given":"Marijana","family":"Milovic","sequence":"additional","affiliation":[{"name":"Clinic for Medical Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Krivokuca","sequence":"additional","affiliation":[{"name":"Department for Genetic Counseling for Hereditary Cancer, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Roht, L., Laidre, P., Tooming, M., T\u00f5nisson, N., N\u00f5ukas, M., Nurm, M., Roomere, H., Rekker, K., Toome, K., and Fjodorova, O. 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