Origin licensing builds a fundamental basis for genome stability in DNA 
replication. Recent studies reported that deregulation of origin licensing is 
associated with replication stress in precancerous lesions. The heterohexameric 
complex of minichromosome maintenance proteins (MCM2-7 complex) plays an 
essential role in origin licensing. Previously, we reported the recovery of the 
first viable Mcm mutant allele (named Mcm4(Chaos3)) in mice. The Mcm4(Chaos3) 
allele destabilizes the MCM2-7 complex, leading to chromosome instability and 
the formation of spontaneous tumors in Mcm4(Chaos3) homozygous mice. Supporting 
our finding, a recent study reported that mice with reduced expression of MCM2 
die with lymphomas within the first few months after birth. These data strongly 
suggest that mutant Mcm2-7 genes are cancer-causing genes with nearly complete 
penetrance in mice. This could be the case for humans as well. Nevertheless, 
related investigations have not been undertaken due to the essential nature of 
the MCM2-7 genes. To circumvent this problem, we focused on the variant alleles 
of human MCM2-7 genes derived from single nucleotide polymorphisms. We created a 
total of 14 variant alleles in the corresponding genes in Saccharomyces 
cerevisiae. The phenotypic consequence was assayed for minichromosome loss, a 
surrogate phenotype for genome instability and cancer susceptibility. This 
screen identified a MCM5 variant allele with pathogenic potential. This allele 
deserves further investigations on its effect on cancer development in human 
populations.