Somatic TP53 variants frequently confound germ-line testing results. - PubMed - NCBI
Genet Med. 2017 Nov 30. doi: 10.1038/gim.2017.196. [Epub ahead of print]
Somatic TP53 variants frequently confound germ-line testing results.
Weitzel JN1,
Chao EC2,3,
Nehoray B1,
Van Tongeren LR1,
LaDuca H2,
Blazer KR1,
Slavin T,
Facmg DABMD1,
Pesaran T2,
Rybak C1,
Solomon I1,
Niell-Swiller M1,
Dolinsky JS2,
Castillo D1,
Elliott A2,
Gau CL2,
Speare V2,
Jasperson K2.
Abstract
PurposeBlood/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.MethodsPathogenic 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.ResultsAmong 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).ConclusionACE 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.GENETICS in MEDICINE advance online publication, 30 November 2017; doi:10.1038/gim.2017.196.
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