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Genetic counseling is already implemented for known high\u2010risk variants; however, the majority of CRC are of unknown causes. In our study, 110 CRC patients in 55 Swedish families with a strong history of CRC but unknown genetic causes were analyzed with the aim of identifying novel candidate CRC predisposing genes. Exome sequencing was used to identify rare and high\u2010impact variants enriched in the families. No clear pathogenic variants were found in known CRC predisposing genes; however, potential pathogenic variants in novel CRC predisposing genes were identified. Over 3000 variants with minor allele frequency (MAF) &lt;0.01 and Combined Annotation Dependent Depletion (CADD)\u2009&gt;\u200920 were seen aggregating in the CRC families. Of those, 27 variants with MAF\u2009&lt;\u20090.001 and CADD&gt;25 were considered high\u2010risk mutations. Interestingly, more than half of the high\u2010risk variants were detected in three families, suggesting cumulating contribution of several variants to CRC. In summary, our study shows that despite a strong history of CRC within families, identifying pathogenic variants is challenging. In a small number of families, few rare mutations were shared by affected family members. This could indicate that in the absence of known CRC predisposing genes, a cumulating contribution of mutations leads to CRC observed in these families.<\/jats:p>","DOI":"10.1002\/ijc.33567","type":"journal-article","created":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T09:07:47Z","timestamp":1615972067000},"page":"627-634","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of known and novel familial cancer genes in Swedish colorectal cancer families"],"prefix":"10.1002","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4352-152X","authenticated-orcid":false,"given":"Hafdis T.","family":"Helgadottir","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Surgery Karolinska Institute  Stockholm Sweden"},{"name":"Department of Clinical Genetics Karolinska University Hospital  Stockholm 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