**5. Conclusions**

The results of our study provide support to the recommendation that *RET* genetic screening should be performed in all MTC cases, regardless of the family history of patients and their clinical presentation, and according to the appropriateness of ATA's guidelines for clinical management of carriers of MOD risk level mutations. It is also highlighted that *RET* molecular analysis leads to the detection of a substantial proportion of variants associated with unknown risks, which poses serious challenges to the counselling and management of the patients and the family. However, co-segregation analysis in the family, genotype/phenotype analysis and a careful revision of the databases and literature proves helpful, at least in some of the cases, in order to tentatively assign the case to one of the known risk classes and inform management accordingly. This approach led us to provide evidence supporting the classification of p.Ser904Phe as the lowest risk level variant and of p.Asp631\_Leu633delinsGlu as a novel variant responsible for MEN2B of HST/H risk level.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/2072-6694/12/11/3268/s1, Table S1: Case series under study.

**Author Contributions:** Conceptualization: D.T. and G.I.; methodology: D.T., G.I., C.R., L.G.; patient identification and clinical characterization: A.R., D.B., D.M., M.E.C., U.P., A.P. (Antonio Percesepe), A.P. (Andrea Pession); data curation: M.R.; writing—original draft preparation: G.I., D.T.; writing—review and editing: C.R. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
