Suspected clonal hematopoiesis as a natural functional assay of TP53 germline variant pathogenicity.
Genet Med
; 24(3): 673-680, 2022 03.
Article
em En
| MEDLINE
| ID: mdl-34906512
ABSTRACT
PURPOSE:
Some variants identified by multigene panel testing of DNA from blood present with low variant allele fraction (VAF), often a manifestation of clonal hematopoiesis. Research has shown that the proportion of variants with low VAF is especially high in TP53, the Li-Fraumeni syndrome gene. Based on the hypothesis that variants with low VAF are positively selected as drivers of clonal hematopoiesis, we investigated the use of VAF as a predictor of TP53 germline variant pathogenicity.METHODS:
We used data from 260,681 TP53 variants identified at 2 laboratories to compare the distribution of pathogenic and benign variants at different VAF intervals.RESULTS:
Likelihood ratios toward pathogenicity associated with a VAF < 26% equated to the American College of Medical Genetics/Association of Molecular Pathology strong strength level and were applicable for 1 in 5 variants of unknown significance.CONCLUSION:
In conclusion, detection of variants with low VAF in blood can be considered an in vivo functional assay to aid assessment of TP53 variant pathogenicity.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Predisposição Genética para Doença
/
Hematopoiese Clonal
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article