BUB1 is a mitotic serine-threonine protein kinase that functions with a complex of proteins to support proper chromosomal segregation and kinetochore binding. Loss of function variants in BUB1 have been implicated in chromosomal segregation errors and aneuploidy. Biallelic BUB1 mutations are associated with primary microcephaly-30 (MCPH30). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability; therefore the autosomal recessive condition has been split and this curation solely focuses on autosomal dominant colorectal cancer. Germline variants in BUB1 were first reported in humans with colorectal cancer as early as 2013 (de Voer, et al., PMID: 23747338). At least 5 variants (truncating, missense, and splicing variants) identified in 5 individuals with colon cancer from 2 publications were included in this curation (2.7 points, PMID: 23747338, 29448935). These individuals were noted to have polyposis, mosaic aneuploidy, and/or mild dysmorphic features. However, a case-control study (PMID:27713038) found no evidence supporting BUB1 and hereditary colorectal cancer (scored as contradictory evidence). Experimental evidence was included in this curation (1 point, PMIDs: 9521327, 11283619). Co-immunoprecipitation assay demonstrated that BUB1 interacts with APC. Colorectal cancer cell lines with BUB1 mutations showed chromosomal instability. In summary, there is limited evidence to support this gene-disease relationship of BUB1 and autosomal dominant colorectal cancer. This curation was approved by the ClinGen Hereditary Cancer GCEP on 6/23/2023 (SOP Version 9). Summary of Genetic Evidence: 2.7 points; Experimental Evidence: 1 point; Total: 3.7 points.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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