ABSTRACT Objectives: To assess the molecular profile of follicular cell-derived thyroid carcinomas (FCDTCs) and correlate the identified mutations with the clinical and pathological features of the affected patients. Materials and methods: Cross-sectional study of tumor samples from 100 adult patients diagnosed with FCDTC between 2010 and 2019. The patients’ clinical and pathological data were collected. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumors using the ReliaPrep FFPE gDNA Miniprep System. Genotyping of target genomic regions (KRAS, NRAS, BRAF, EGFR, and PIK3CA) was performed using the AmpliSeq panel, while sequencing was performed on the iSeq 100 platform. Results: The patients’ mean age was 39 years. In all, 82% of the tumors were classic papillary thyroid carcinomas. Overall, 54 (54%) tumor samples yielded satisfactory results on next-generation sequencing (NGS), of which 31 harbored mutations. BRAF gene mutations were the most frequent, with the BRAFV600E mutation present in 10 tumors. Seven tumors had BRAFNON-V600E mutations not previously described in FCDTCs (G464E, G464R, G466E, S467L, G469E, G596D, and the T599Ifs*10 deletion) but described in other types of cancer (i.e., skin/melanoma, lung, colorectal, and others). One tumor had a previously reported BRAFA598V mutation. EGFR gene mutations were found in 16 (29%) and KRAS or NRAS alterations in 8 (14%) of the 54 tumors analyzed. Conclusion: We described herein seven non-hotspot/novel variants in the BRAF gene, highlighting their potential role in expanding our understanding of FCDTC genetics. Objectives cellderived cell derived (FCDTCs methods Crosssectional Cross sectional 201 2019 collected formalinfixed, formalinfixed formalin fixed, fixed formalin-fixed paraffinembedded paraffin embedded (FFPE System KRAS, (KRAS PIK3CA PIKCA PIK CA panel platform Results 3 years all 82 Overall 5 54% (54% nextgeneration next generation NGS, NGS , (NGS) frequent BRAFVE BRAFV E 1 BRAFNONV600E BRAFNONVE BRAFNON V600E V G464E, G464E GE G (G464E G464R GR R G466E S467L SL S L G469E G596D GD D T599Ifs10 TIfs T599Ifs T Ifs T599Ifs*1 deletion i.e., ie i e (i.e. skinmelanoma skin melanoma skin/melanoma lung colorectal others. others . others) BRAFAV BRAFA 29% 29 (29% 14% 14 (14% analyzed Conclusion nonhotspot/novel nonhotspotnovel non hotspot/novel hotspot novel genetics 20 (54 (NGS BRAFNONV VE T599Ifs1 T599Ifs* i.e. (i.e 2 (29 (14 nonhotspot hotspotnovel (5 i.e (2 (1 (