The MC1R gene is a key regulator of skin pigmentation. We aimed to evaluate the 
association between MC1R variants and the risk of sporadic cutaneous melanoma 
(CM) within the M-SKIP project, an international pooled-analysis on MC1R, skin 
cancer and phenotypic characteristics. Data included 5,160 cases and 12,119 
controls from 17 studies. We calculated a summary odds ratio (SOR) for the 
association of each of the nine most studied MC1R variants and of variants 
combined with CM by using random-effects models. Stratified analysis by 
phenotypic characteristics were also performed. Melanoma risk increased with 
presence of any of the main MC1R variants: the SOR for each variant ranged from 
1.47 (95%CI: 1.17-1.84) for V60L to 2.74 (1.53-4.89) for D84E. Carriers of any 
MC1R variant had a 66% higher risk of developing melanoma compared with 
wild-type subjects (SOR; 95%CI: 1.66; 1.41-1.96) and the risk attributable to 
MC1R variants was 28%. When taking into account phenotypic characteristics, we 
found that MC1R-associated melanoma risk increased only for darker-pigmented 
Caucasians: SOR (95%CI) was 3.14 (2.06-4.80) for subjects with no freckles, no 
red hair and skin Type III/IV. Our study documents the important role of all the 
main MC1R variants in sporadic CM and suggests that they have a direct effect on 
melanoma risk, independently on the phenotypic characteristics of carriers. This 
is of particular importance for assessing preventive strategies, which may be 
directed to darker-pigmented Caucasians with MC1R variants as well as to lightly 
pigmented, fair-skinned subjects.