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Genet."],"published-print":{"date-parts":[[2026,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Variants of uncertain significance (VUS) are genetic variations with unclear clinical implications, often complicating clinical management in genetic testing. The analysis of co-segregation of the variant with the disease in families has been shown to be a powerful tool for the classification of these variants. We present CAL-Leiden (Co-segregation Analysis via Likelihood ratio analysis-Leiden), a comprehensive co-segregation model facilitating the classification of variants in\n                    <jats:italic>BRCA1<\/jats:italic>\n                    ,\n                    <jats:italic>BRCA2<\/jats:italic>\n                    and\n                    <jats:italic>PALB2<\/jats:italic>\n                    genes, which can be used as an important component of the ACMG\/AMP (the American College of Medical Genetics and Genomics\/ the Association for Molecular Pathology) classification guideline. CAL-Leiden includes an expanded range of cancer types, including pancreatic cancer, in addition to breast and ovarian cancer. The model operates on a multiple-cancers-per-individual framework, so that likelihood contributions account for all relevant cancers observed in a person, including contralateral breast cancer. The model integrates population incidence rates from the Netherlands, the United Kingdom and United States, along with penetrance data from the latest literature. A web-based platform has been developed, making the model accessible and practical for use in diagnostic labs:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/bioexp.net\/cosegregation\/\" ext-link-type=\"uri\">https:\/\/bioexp.net\/cosegregation\/<\/jats:ext-link>\n                    . We demonstrate the functionality of the tool with multiple pedigrees and compare its performance with alternative approaches. The features in CAL-Leiden collectively contribute to a more comprehensive and accurate assessment of variant pathogenicity, helping clinical laboratory specialists and researchers in classification of the variants of uncertain significance.\n                  <\/jats:p>","DOI":"10.1007\/s00439-025-02816-z","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T03:55:08Z","timestamp":1774497308000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A comprehensive and accessible model for co-segregation analysis in BRCA1, BRCA2, and PALB2 variant classification"],"prefix":"10.1007","volume":"145","author":[{"given":"Setareh","family":"Moghadasi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramin","family":"Monajemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merel E.","family":"Braspenning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maaike P. 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Now it has been corrected.","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2026","order":8,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":9,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":10,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1007\/s00439-026-02844-3","URL":"https:\/\/doi.org\/10.1007\/s00439-026-02844-3","order":11,"name":"change_details","label":"Change Details","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":"Conflict of interest"}},{"value":"Not applicable. Simulated pedigrees are used.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"34"}}