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Genet Med. 2018 Aug;20(8):809-816. doi: 10.1038/gim.2017.196. Epub 2017 Nov 30.

Somatic TP53 variants frequently confound germ-line testing results.

Author information

1
Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA. jweitzel@coh.org.
2
Ambry Genetics, Aliso Viejo, California, USA.
3
Department of Pediatrics, University of California, Irvine, Irvine, California, USA.
4
Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA.

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.

KEYWORDS:

Li-Fraumeni syndrome; TP53; aberrant clonal expansion; clonal hematopoiesis; somatic variant

PMID:
29189820
PMCID:
PMC5976505
DOI:
10.1038/gim.2017.196
[Indexed for MEDLINE]
Free PMC Article

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