The clinical significance of small TP53 clones detected with next generation sequencing (NGS) in chronic lymphocytic leukemia is an issue of active debate. According to the official guidelines, treatment decisions should be guided only by variants with variant allele frequency (VAF) ≥10%. We present data on 325 consecutive patients with chronic lymphocytic leukemia analyzed with NGS. In total 47 pathogenic/likely pathogenic (P/LP), TP53 variants were detected in 26 patients (8%). Eleven of these (23%) were in the 5% to 10% VAF range and reported according to our institutional policy. All TP53 variants in the 5% to 10% VAF range were confirmed (100% concordance) with a second NGS panel. Our results where further validated with the performance of Sanger sequencing and digital droplet PCR (ddPCR). In 12 patients with available fluorescence in situ hybridization data and TP53 mutations within 5% to 10% VAF, deletion of chromosome 17p (del(17p)) was detectable in only 1 patient. We propose a robust diagnostic algorithm, which allows the safe detection and reporting of TP53 variants with VAF down to 5% in the clinical setting. Our study provides evidence that NGS is equally potent to detect variants with VAF 5% to 10% compared to those with VAF 10% to 15%, highlighting the urgent need for harmonization of NGS methodologies across diagnostic laboratories.