An ERIC (European research initiative on CLL http://www.ericll.org/) multicenter study on the prognostic and predictive impact of low-burden TP53 mutations is in progress with three phases: 1) compare results among laboratories performing NGS analysis of TP53 mutations in CLL with a detection limit of ≤1% VAF, 2) assess the prognostic and predictive impact of low-VAF TP53 variants in patients entering first-line treatment, and 3) re-evaluate the cut-off for reporting of TP53 variants in CLL and, if needed, to update recommendations on minor TP53 variant detection, validation, and reporting. The gene discussed is TP53; the disease is B-cell chronic lymphocytic leukemia.