Clinical features and outcomes of MEN2A with RET codon 634 pathogenic variants

Germline RET codon 634 pathogenic variants (PVs) are at high-risk for early-onset medullary thyroid carcinoma (MTC), but prior reports suggest that RET p.C634R PV may confer a more aggressive phenotype.

We compared MEN2A phenotype and MTC outcomes with germline RET p.C634R vs other RET p.C634X PVs. We conducted a retrospective single-center cohort study of patients harboring a germline RET p.C634 PV, enrolled in the MTC Collaborative Registry (MTCCoRe) and seen at least once between May 2012 and May 2024.

One hundred and thirty-five patients included: p.C634R (n = 60) and other p.C634X variants (n = 75). The p.C634R PV was associated with higher penetrance of pheochromocytoma (PHEO) (67% vs 37%, P < .001) and primary hyperparathyroidism (PHPT) (30% vs 15%, P = .036). Prevalence of MTC (87% vs 80%, P = .362), cutaneous lichen amyloidosis (17% vs 9% P = .296), and median age at initial thyroidectomy (18 vs 20 years, P = .479) did not differ significantly between groups. Medullary thyroid carcinoma characteristics, including stage, multifocality, extrathyroidal extension, vascular invasion, lymph node metastases, and distant metastases, were comparable. There were no significant differences in disease-free survival, overall survival, or distant metastasis-free survival for MTC. Disease status at last follow-up also was similar between p.C634R and other p.C634X PVs: no evidence of disease in 43% vs 62% (P = .059), biochemical evidence of disease in 25% vs 17% (P = .226), and structural evidence of disease in 27% vs 20% (P = .298).

In this large single-center cohort, germline RET p.C634R was associated with a higher penetrance of PHEO and PHPT but did not increase MTC aggressiveness or worsen clinical outcomes compared with other RET p.C634 PVs.