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Thyroid cancer is the most common endocrine malignant tumor. Medullary thyroid carcinoma (MTC) is an aggressive tumor arising from calcitonin-producing parafollicular cells. MTC has autosomal dominant inheritance and accounts for 5-10 % of all thyroid cancers. It occurs in hereditary (25 %, hMTC) and sporadic (75 %, sMTC) forms. Gain-of-function mutations in the REarranged during transfection (RET) proto-oncogene have been identified in 98 % of hMTC and 50 % of sMTC. The aim of this investigation was to identify mutation(s) in the much conserved RET exon10 in Iranian MTC patients. We started screening patients with MTC for RET in 2001. This study included 347 individuals (154 with sMTC, 38 with FMTC, 8 with multiple endocrine neoplasia type 2A [MEN2A], 3 with MEN2B, and 3 with pheochromocytoma; 207 index cases and 140 relatives). Germline mutation screening of RET exon10 was performed with PCR-DNA sequencing. A total of 14 missense mutations (10 mutations in men and 4 in women) were identified in cysteine codons 611, 618, and 620 (exon10) in 11 patients and three first-degree relatives as follows: four C611Y (three with FMTC and one relative), one C618R (FMTC), one C618S (sMTC), one C620G (sMTC), four C620R (one with FMTC and three with sMTC), and three C620F (one with FMTC and two relatives). In the present study, six different mutations were identified in exon10 of RET in 14 patients with sMTC and FMTC that were restricted to codons 611, 618, and 620, but not in codon 609. This data showed a skewed pattern of RET exon10 mutation compared to other populations. No mutation was found for MEN2A, MEN2B, and pheochromocytoma in exon10 in this population. In the most common mutations in exon10, the FMTC and sMTC patients were C611Y and C620R, respectively.