Background: Acute Myeloid Leukemia (AML) is a devastating disease with poor overall survival. Access to precision medicines, is revolutionizing AML care and is driving an increase in Next Generation Sequencing (NGS) utilization to determine the genomic profile of patients with AML. Advanced analysis into the interplay between mutational status for multiple genes is granting access to new targeted and precision medicine treatment options with improved outcomes. Methods: Rate of NGS adoption and TP53 mutation status were determined for a cohort of 984 AML patients tested by NGS from the Diaceutics Diagnostic Index between 2017 and 2019. Mutation rate of other genes on the same NGS panel used to determine if TP53 status was determined and compared using the z-score test for two population proportions. The stability of TP53 and co-mutation status at time of diagnosis and relapse/refractory was also analyzed. Results: We have seen a 2-fold increase in the average routine clinical practice uptake of NGS in a representative real-world patient cohort (Q3 2017, n = 144; Q3 2019, n = 290). In a cohort of 984 AML patients tested by NGS 151 (15.3%) had a TP53 mutation (Exon 4-9). Of those that had a TP53 mutation, significant negative associations were observed with mutations in seven other genes (ASXL1 p = 0.00308, CEBPA p = 0.0027, FLT3 p < 0.00001, IDH1 p = 0.04338, NRAS p = 0.0012, RUNX1 p = 0.01878 and TET2 p = 0.0251). There were no statistically significant differences in TP53 mutation and other gene mutation rates between diagnosis and relapse/refractory timepoints. Conclusions: This data suggests that TP53 and other gene co-mutants may act in similar activation pathways resulting in rare detection. One possibility is that double mutants result in synthetic lethality leading to a low clonal population. Second, when co-mutated clones escape immune surveillance and regulation, it results in particularly aggressive leukemias with lower overall survival. The stability of TP53 and co-mutation is relatively stable, which has implications for testing algorithms and clinical utility as a marker of MRD. Although a clinical trial may be difficult due to low numbers of patients, a TP53 antagonist and targeted therapy may be a valuable treatment option in rare cases where co-mutation does exist.