Alternatively, the distinction between high-risk cancer susceptibility variants that undergo a somatic second hit and low-risk alleles that do not—even where bi-allelic loss appears to convey a clear oncogenic advantage, as demonstrated in the case of NTHL1 by the recessive cancer syndrome—directly reflects the fact that these alleles are less prone to obtain a second hit leading to a complete loss of the function, and always retain some activity in the tumor. This evidence concerns the gene NTHL1 and neoplasm.