Back to Publications

Somatic TP53 variants frequently confound germline testing results.

Specialty Areas:
Date: January 10, 2018
Authors:
Aaron Elliott, Bita Nehoray, Chia-Ling Gau, PhD, DABMG, Christina Rybak, Danielle Castillo, Elizabeth C. Chao, Holly Laduca, Ilana Solomon, Jeffrey Weitzel, Jill Dolinsky, Kathleen R Blazer, Kory Jasperson, Lily R Van Tongeren, Mariana Niell-Swiller, Thomas P. Slavin, Tina Pesaran, MA, MS, CGC, Virginia Speare
Journal: Genetics in Medicine
Read Abstract

Abstract

Purpose

Blood/saliva DNA is thought to represent the germ line in genetic cancer-risk assessment. Cases with pathogenic TP53 variants detected by multigene panel testing are often discordant with Li-Fraumeni syndrome, raising concern about misinterpretation of acquired aberrant clonal expansions (ACEs) with TP53 variants as germ-line results.

Methods

Pathogenic TP53 variants with abnormal next-generation sequencing metrics (e.g., decreased ratio (<25%) of mutant to wild-type allele, more than two detected alleles) were selected from a CLIA laboratory testing cohort. Alternate tissues and/or close relatives were tested to distinguish between ACE and germ-line status. Clinical data and Li-Fraumeni syndrome testing criteria were examined.

Results

Among 114,630 multigene panel tests and 1,454 TP53 gene-specific analyses, abnormal next-generation sequencing metrics were observed in 20% of 353 TP53-positive results, and ACE was confirmed for 91% of cases with ancillary materials, most of these due to clonal hematopoiesis. Only four met Chompret criteria. Individuals with ACE were older (50 years vs. 33.7; P = 0.02) and were identified more frequently in multigene panel tests (66/285; 23.2%) than in TP53 gene-specific tests (6/68; 8.8%, P = 0.005).

Conclusion

ACE confounds germ-line diagnosis, may portend hematologic malignancy, and may provoke unwarranted clinical interventions. Ancillary testing to confirm germ-line status should precede Li-Fraumeni syndrome management.