An updated quantitative model to classify missense variants in the TP53 gene: A novel multifactorial strategy.
Hum Mutat
; 42(10): 1351-1361, 2021 10.
Article
em En
| MEDLINE
| ID: mdl-34273903
ABSTRACT
Multigene panel testing has led to an increase in the number of variants of uncertain significance identified in the TP53 gene, associated with Li-Fraumeni syndrome. We previously developed a quantitative model for predicting the pathogenicity of P53 missense variants based on the combination of calibrated bioinformatic information and somatic to germline ratio. Here, we extended this quantitative model for the classification of P53 predicted missense variants by adding new pieces of evidence (personal and family history parameters, loss-of-function results, population allele frequency, healthy individual status by age 60, and breast tumor pathology). We also annotated which missense variants might have an effect on splicing based on bioinformatic predictions. This updated model plus annotation led to the classification of 805 variants into a clinically relevant class, which correlated well with existing ClinVar classifications, and resolved a large number of conflicting and uncertain classifications. We propose this model as a reliable approach to TP53 germline variant classification and emphasize its use in contributing to optimize TP53-specific ACMG/AMP guidelines.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Genes p53
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Síndrome de Li-Fraumeni
Tipo de estudo:
Guideline
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Prognostic_studies
Limite:
Humans
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Middle aged
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article