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Simple Summary: The mutational load of BRAFV600E in melanomas has been described as a possible prognostic biomarker but there is no information about the mutant allele frequency (MAF) variability of BRAFV600E within cutaneous melanomas and its potential prognostic implications. Our study suggests that the variation degree of BRAFV600E MAF within primary cutaneous melanoma could act as a determinant in the location of primary melanomas as well as their first metastases and could influence prognostic indicators such as Breslow and mitotic indexes. BRAFV600E MAF variation is also related to the neoplastic cell phenotype and tumor lymphocytic infiltrate of primary tumors. For all these reasons, detection of BRAFV600E MAF variation could be a useful prognostic biomarker. It is worth exploring the role of BRAFV600E MAF variation with regards to the response of melanoma to targeted therapies. Background: Cutaneous melanoma shows high variability regarding clinicopathological presentation, evolution and prognosis. Methods: Next generation sequencing was performed to analyze hotspot mutations in different areas of primary melanomas (MMp) and their paired metastases. Clinicopathological features were evaluated depending on the degree of variation of the BRAFV600E mutant allele frequency (MAF) in MMp. Results: In our cohort of 14 superficial spreading, 10 nodular melanomas and 52 metastases, 17/24 (71%) melanomas had a BRAFV600E mutation and 5/24 (21%) had a NRASQ61 mutation. We observed a high variation of BRAFV600E MAF (H-BRAFV600E) in 7/17 (41%) MMp. The H-BRAFV600E MMp were all located on the trunk, had lower Breslow and mitotic indexes and predominantly, a first nodal metastasis. Regions with spindled tumor cells (Spin) and high lymphocytic infiltrate (HInf) were more frequent in the H-BRAFV600E patients (4/7; 57%), whereas regions with epithelial tumor cells (Epit) and low lymphocytic infiltrate (LInf) were predominant (6/10; 60%) and exclusive in the low BRAFV600E MAF variation tumors (L-BRAFV600E). The H-BRAFV600E/Spin/HInf MMp patients had better prognostic features and nodal first metastasis. Conclusions: The H-BRAFV600E MMp were located on the trunk, had better prognostic characteristics, such as lower Breslow and mitotic indexes as well as high lymphocytic infiltrate. [ABSTRACT FROM AUTHOR]