Increasing availability of genomic testing poses new challenges to clinicians, particularly where variant interpretation from commercial sources may be equivocal. We report a patient with recurrent rhabdomyosarcoma and subsequent bilateral breast cancer who was found to harbor a previously undescribed germline TP53 sequence alteration annotated by the commercial laboratory as a variant of uncertain significance (VUS). By investigating publically available databases of aggregated normal germline and malignant somatic genomic sequences, we conclude that this missense variant, c.476C>T (p.A159V), is a novel, pathogenic Li-Fraumeni syndrome mutation, and illustrate the utility of these resources in clinical pediatric hematology and oncology practice.