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The detected variants were processed by bioinformatics filtering and prioritization, including STRING protein\u2013protein interaction and pathway analysis. A total of 150 missense, 19 stop\u2010gain, 22 frameshift and 13 canonical splice site variants fulfilled our filtering criteria. The STRING analysis identified 20 DNA repair\/cell cycle proteins as the main cluster, related to genes <jats:italic>CHEK2<\/jats:italic>, <jats:italic>EXO1<\/jats:italic>, <jats:italic>FAAP24<\/jats:italic>, <jats:italic>FANCI<\/jats:italic>, <jats:italic>MCPH1<\/jats:italic>, <jats:italic>POLL<\/jats:italic>, <jats:italic>PRC1<\/jats:italic>, <jats:italic>RECQL<\/jats:italic>, <jats:italic>RECQL5<\/jats:italic>, <jats:italic>RRM2<\/jats:italic>, <jats:italic>SHCBP1<\/jats:italic>, <jats:italic>SMC2<\/jats:italic>, <jats:italic>XRCC1<\/jats:italic>, in addition to <jats:italic>CDK18<\/jats:italic>, <jats:italic>ENDOV<\/jats:italic>, <jats:italic>ZW10<\/jats:italic> and the known mismatch repair genes. Another STRING network included extracellular matrix genes and TGF\u03b2 signaling genes. In the nine whole\u2010exome sequenced patients, eight harbored at least two candidate DNA repair\/cell cycle\/TGF\u03b2 signaling gene variants. The number of families is too small to provide evidence for individual variants but, considering the known role of DNA repair\/cell cycle genes in CRC, the clustering of multiple deleterious variants in the present families suggests that these, perhaps jointly, contributed to CRC development in these families.<\/jats:p>","DOI":"10.1002\/ijc.35283","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T09:23:35Z","timestamp":1733822615000},"page":"1393-1403","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Search for germline gene variants in colorectal cancer families presenting with multiple primary colorectal cancers"],"prefix":"10.1002","volume":"156","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9857-4728","authenticated-orcid":false,"given":"Asta","family":"F\u00f6rsti","sequence":"first","affiliation":[{"name":"Hopp Children's Cancer Center (KiTZ)  Heidelberg 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