Interpreting <i>TP53</i> variants: somatic mosaicism and <i>ERCC6L2</i>-driven clonal evolution.

Abstract

We present two illustrative cases highlighting diagnostic, surveillance and management complexities of <i>TP53</i> pathogenic variants (PVs). Case 1 describes a 24-year-old female with early-onset breast cancer and a somatic mosaic <i>TP53</i> PV with a variant allele frequency of 19% in blood, initially missed by panel sequencing. Case 2 concerns a 59-year-old female with multiple primary tumours and two identical <i>TP53</i> variants detected in two different tissues which initially suggested somatic mosaicism but were consistent with a myelodysplastic syndrome-related clone secondary to homozygous germline <i>ERCC6L2</i>-associated bone marrow failure. These cases highlight the importance of accurately interpreting <i>TP53</i> variants for correct clinical decision-making. Contextual factors such as age, phenotype, family history and tissue testing must guide diagnosis, treatment and surveillance.