Somatic TP53 variants frequently confound germline testing results

PURPOSE: Blood/saliva DNA is thought to represent the germline in genetic cancer risk assessment. Cases with pathogenic TP53 variants detected by multi-gene panel tests (MGPT) are often discordant with Li-Fraumeni Syndrome (LFS), raising concern about misinterpretation of acquired aberrant clonal expansions (ACE) with TP53 variants as germline results. METHODS: Pathogenic TP53 variants with abnormal next-generation sequencing (NGS) metrics (e.g., decreased ratio [<25%] of mutant to wild-type allele, >2 detected alleles) were selected from a CLIA laboratory testing cohort. Alternate tissues and/or close relatives were tested to discern between ACE and germline status. Clinical data and LFS testing criteria were examined. RESULTS: Among 114,630 MGPT and 1,454 TP53 gene-specific analyses, abnormal NGS metrics were observed in 20% of 353 TP53 positive results, and ACE was confirmed for 91% of cases with ancillary materials, most due to clonal hematopoiesis. Only four met Chompret criteria. ACE cases were older (50 years vs 33.7; P = 0.02) and were more frequent among MGPT (66/285; 23.2%) vs TP53 gene-specific tests (6/68; 8.8%, P = 0.005). CONCLUSION: ACE confounds germline diagnosis, may portend hematologic malignancy, and may result in unwarranted clinical interventions. Ancillary testing to confirm germline status should precede Li-Fraumeni syndrome management.