In addition, as somatic VHL inactivation occurs in most clear cell RCC, and this histopathology accounts for ∼75% of all sporadic RCC, it is not unexpected that genetic modifiers of VHL disease RCC risk, might also function as low penetrance RCC susceptibility alleles (e.g. the association between MMP1/MMP3 hapolotypes and RCC). This evidence concerns the gene VHL and renal cell carcinoma.