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However, comprehensive germline genetic data from indigenous African populations remain scarce. This study aimed to explore germline genetic factors contributing to early-onset CRC (eoCRC) in Indigenous African patients using whole exome sequencing (WES).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      We performed WES on blood-derived genomic DNA from 32 Indigenous African patients diagnosed with eoCRC (&lt;\u200950 years), who previously tested negative on a multigene CRC panel. While preliminary but definitive, pathogenic variants were identified in only 5 patients (16%) across genes such as\n                      <jats:italic>C6<\/jats:italic>\n                      ,\n                      <jats:italic>FAT1<\/jats:italic>\n                      ,\n                      <jats:italic>LZTR1<\/jats:italic>\n                      ,\n                      <jats:italic>PYCR1<\/jats:italic>\n                      , and\n                      <jats:italic>UGT1A7<\/jats:italic>\n                      . A substantial proportion (47%,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200915) carried variants of uncertain significance (VUS) with strong pathogenic potential (\u201cleaning pathogenic\u201d) in genes\n                      <jats:italic>ASXL1<\/jats:italic>\n                      ,\n                      <jats:italic>CHEK2<\/jats:italic>\n                      ,\n                      <jats:italic>ERBB2<\/jats:italic>\n                      ,\n                      <jats:italic>ERCC4<\/jats:italic>\n                      ,\n                      <jats:italic>INSR<\/jats:italic>\n                      ,\n                      <jats:italic>KIT<\/jats:italic>\n                      ,\n                      <jats:italic>MITF<\/jats:italic>\n                      ,\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      ,\n                      <jats:italic>NOTCH2<\/jats:italic>\n                      ,\n                      <jats:italic>PDGFRA<\/jats:italic>\n                      ,\n                      <jats:italic>RAD51B<\/jats:italic>\n                      ,\n                      <jats:italic>RAD54L<\/jats:italic>\n                      ,\n                      <jats:italic>RASA1<\/jats:italic>\n                      ,\n                      <jats:italic>RECQL<\/jats:italic>\n                      ,\n                      <jats:italic>SUFU<\/jats:italic>\n                      ,\n                      <jats:italic>VEGFA<\/jats:italic>\n                      , and\n                      <jats:italic>WT1<\/jats:italic>\n                      . Comparative analysis with public datasets and recurrent findings suggests these leaning pathogenic VUSs may represent true disease-associated variants, currently may be misclassified due to limited representation of African genomes in reference databases.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings reveal a high burden of potentially pathogenic VUSs in indigenous African patients with eoCRC, reflecting both unique genetic architecture and a critical gap in global genomic equity. These variants may contribute to future variant reclassification and improved understanding of CRC predisposition in African populations. This study underscores the urgent need for population-specific genomic research and the development of inclusive variant databases to support accurate diagnosis and personalised care.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11033-025-10750-6","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T10:00:20Z","timestamp":1751968820000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["High burden of variants of uncertain significance in early-onset colorectal cancer among indigenous African patients: a call for global research equity in cancer genetics"],"prefix":"10.1007","volume":"52","author":[{"given":"Safiye","family":"Yildiz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramadhani","family":"Chambuso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Rebello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5688-1634","authenticated-orcid":false,"given":"Raj","family":"Ramesar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,8]]},"reference":[{"issue":"3","key":"10750_CR1","doi-asserted-by":"publisher","first-page":"233","DOI":"10.3322\/caac.21772","volume":"73","author":"RL Siegel","year":"2023","unstructured":"Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A (2023) Colorectal cancer statistics, 2023. 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