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BUB1 – Colorectal Cancer

Heterozygous germline variants in BUB1 have been identified in a small subset of early-onset and familial colorectal cancer (CRC) patients, suggesting a possible autosomal dominant predisposition mechanism. In a study of 208 early-onset or familial CRC cases, 2.9% harbored BUB1 or BUB3 mutations, including frameshift and splice‐site alterations, without consistent aneuploidy or dysmorphic features (PMID:23747338). Subsequent screening of 456 hereditary non-polyposis CRC and 88 polyposis families found only four rare BUB1 variants (one splice-site c.1965-1G>A and three missense), with minimal segregation data and no mosaic variegated aneuploidy reported (PMID:29448935). The recurrent variant c.2473C>T (p.Pro825Ser) was reported but remains of uncertain significance.

Functional studies demonstrate that BUB1 kinase activity is critical for spindle checkpoint fidelity: Bub1 phosphorylates Cdc20 to inhibit APC/C^Cdc20, and non-phosphorylatable Cdc20 mutants bypass mitotic arrest upon spindle damage (PMID:15525512). However, a 54-year-old man with a 2q13 deletion causing BUB1 haploinsufficiency showed no gastrointestinal tumors or aneuploidy, indicating that BUB1 loss alone is insufficient for colorectal tumorigenesis (PMID:23440991). Overall, current evidence is limited by low variant frequency, sparse segregation, and incomplete in vivo modeling. Key Take-home: While BUB1 variants may modestly increase CRC risk via spindle checkpoint disruption, additional large‐scale familial studies and functional validation are required before routine clinical testing.

References

  • Gastroenterology • 2013 • Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are risk factors for colorectal cancer. PMID:23747338
  • Molecular Cancer • 2018 • Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are infrequent in familial colorectal cancer and polyposis. PMID:29448935
  • Molecular Cell • 2004 • Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint. PMID:15525512
  • BMJ Case Reports • 2013 • Absence of aneuploidy and gastrointestinal tumours in a man with a chromosomal 2q13 deletion and BUB1 monoallelic deficiency. PMID:23440991

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

2.9% of early-onset/familial CRC cases with BUB1 variants (n=208 probands) and sparse segregation data

Genetic Evidence

Limited

Six heterozygous BUB1 variant carriers in early-onset CRC ([PMID:23747338]) and four families in follow-up ([PMID:29448935])

Functional Evidence

Limited

In vitro checkpoint disruption via Cdc20 phosphorylation assays ([PMID:15525512]) but haploinsufficiency alone not tumorigenic in vivo ([PMID:23440991])