*2.2. RET Test Results and Clinical Correlations*

Twelve different *RET* variants were identified in our sample: seven previously classified in a specific risk class (one of HST risk level, two of H risk level, four of MOD risk level) (Table 1) and five unclassified. The HST risk level variant p.Met918Thr was identified in a sporadic case of MEN2B, as well as in an external patient for whom phenotype was not detailed. H risk level variants were identified in two cases of familial MEN2A. MOD risk level variants were found in 34 subjects of 13 families; all belonged to A risk class (the lowest risk level) in the previous classification.


**Table 1.** *RET* classified variants detected in the population under study.

<sup>a</sup> Only carriers with known clinical information were included; <sup>b</sup> Including marfanoid habitus, ganglioneuromatosis of the gut and oral mucosa, mild dysmorphic features. Abbreviations: ATA = American Thyroid Association; MTC = medullary thyroid carcinoma; PCC = pheocromocytoma; PHPT = primary hyperparathyroidism; MOD = moderate; H = high; HST = highest.

Overall, patients with germline *RET* variants significantly differed from those testing negative by the presence of family history (68.2% vs. 2.1%; *p* < 0.001) and by mean age at MTC diagnosis (44.45 vs. 56.42; *p* = 0.010). When comparing carriers of MOD risk variants with wild-type *RET* patients, the presence of family history was still significantly more frequent in the former group (72.2% vs. 2.1%; *p* < 0.001), while mean age at MTC diagnosis did not differ significantly (51.78 vs. 56.42; *p* = 0.281). Indeed, mean age at MTC diagnosis was 51.78 years among carriers of MOD risk variants, compared to 11.5 years in carriers of HST/H risk level variants (*p* < 0.001). The comparison of clinical features of patients with MTC according to test results is shown in Table 2.


**Table 2.** Clinical characteristics of MTC patients according to test result.

<sup>a</sup> Information on stage was available for 29 patients.
