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We describe a multi-generation CRC-affected family segregating pathogenic variants in both <jats:italic>BRCA1<\/jats:italic>, a gene associated with breast and ovarian cancer and <jats:italic>RNF43<\/jats:italic>, a gene associated with Serrated Polyposis Syndrome (SPS). A single family out of 105 families meeting the criteria for FCCTX (Amsterdam I family history criteria with mismatch repair (MMR)-proficient CRCs) recruited to the Australasian Colorectal Cancer Family Registry (ACCFR; 1998\u20132008) that underwent whole exome sequencing (WES), was selected for further testing. CRC and polyp tissue from four carriers were molecularly characterized including a single CRC that underwent WES to determine tumor mutational signatures and loss of heterozygosity (LOH) events. Ten carriers of a germline pathogenic variant <jats:italic>BRCA1<\/jats:italic>:c.2681_2682delAA p.Lys894ThrfsTer8 and eight carriers of a germline pathogenic variant <jats:italic>RNF43<\/jats:italic>:c.988\u00a0C\u2009&gt;\u2009T p.Arg330Ter were identified in this family. Seven members carried both variants, four of which developed CRC. A single carrier of the <jats:italic>RNF43<\/jats:italic> variant met the 2019 World Health Organization (WHO<jats:sup>2019<\/jats:sup>) criteria for SPS, developing a <jats:italic>BRAF<\/jats:italic> p.V600 wildtype CRC. Loss of the wildtype allele for both <jats:italic>BRCA1<\/jats:italic> and <jats:italic>RNF43<\/jats:italic> variants was observed in three CRC tumors while a LOH event across chromosome 17q encompassing both genes was observed in a CRC. Tumor mutational signature analysis identified the homologous recombination deficiency (HRD)-associated COSMIC signatures SBS3 and ID6 in a CRC for a carrier of both variants. Our findings show digenic inheritance of pathogenic variants in <jats:italic>BRCA1<\/jats:italic> and <jats:italic>RNF43<\/jats:italic> segregating with CRC in a FCCTX family. LOH and evidence of BRCA1-associated HRD supports the importance of both these tumor suppressor genes in CRC tumorigenesis.<\/jats:p>","DOI":"10.1007\/s10689-023-00351-2","type":"journal-article","created":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T08:02:06Z","timestamp":1702022526000},"page":"9-21","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Inherited BRCA1 and RNF43 pathogenic variants in a familial colorectal cancer type X family"],"prefix":"10.1007","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1971-8800","authenticated-orcid":false,"given":"James M.","family":"Chan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9852-2103","authenticated-orcid":false,"given":"Mark","family":"Clendenning","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharelle","family":"Joseland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5096-4735","authenticated-orcid":false,"given":"Peter","family":"Georgeson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0980-3646","authenticated-orcid":false,"given":"Khalid","family":"Mahmood","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jihoon E.","family":"Joo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8948-8417","authenticated-orcid":false,"given":"Romy","family":"Walker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Como","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Preston","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuyi Marci","family":"Chai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen Lin","family":"Chu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron L.","family":"Meyers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4840-1095","authenticated-orcid":false,"given":"Bernard J.","family":"Pope","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Duggan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2912-6048","authenticated-orcid":false,"given":"J. Lynn","family":"Fink","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4035-9678","authenticated-orcid":false,"given":"Finlay A.","family":"Macrae","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7671-2651","authenticated-orcid":false,"given":"Christophe","family":"Rosty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8535-6003","authenticated-orcid":false,"given":"Ingrid M.","family":"Winship","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark A.","family":"Jenkins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2225-6675","authenticated-orcid":false,"given":"Daniel D.","family":"Buchanan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,12,8]]},"reference":[{"issue":"2","key":"351_CR1","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1056\/NEJM200007133430201","volume":"343","author":"P Lichtenstein","year":"2000","unstructured":"Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M et al (2000) Environmental and heritable factors in the causation of Cancer \u2014 analyses of cohorts of twins from Sweden, Denmark, and Finland. 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