Taking the advantage of large replication samples, we tested the pairwise genetic epistasis between VAMP5 and MCC. Intriguingly, a significant synergetic interaction between rs1254900 (VAMP5) and rs11241200 (MCC) was identified through the cross-validation by logistic regression and MDR analysis, thereby contributing to the risk of SHSCR. The gene discussed is VAMP5; the disease is Merkel cell skin cancer.