RET and multiple endocrine neoplasia type 2A: These two cases provided the evidence that these two pathogenic mutations together amount to a more deleterious double mutation than that in isolation, which might explain the higher MTC pathogenicity of p.C634Y/V292M/R67H/R982C due to the additive effect of p.V292M/R67H/R982C and p.C634Y in trans. A “second hit” mechanism advocates that allelic imbalance between mutant and wild-type RET is a possible mechanism of tumorigenesis in some patients with MEN 2A-related MTC [40].