The functional impact of variants of uncertain significance in BRCA2.
Genet Med
; 21(2): 293-302, 2019 02.
Article
em En
| MEDLINE
| ID: mdl-29988080
ABSTRACT
PURPOSE:
Genetic testing has uncovered large numbers of variants in the BRCA2 gene for which the clinical significance is unclear. Cancer risk prediction of these variants of uncertain significance (VUS) can be improved by reliable assessment of the extent of impairment of the tumor suppressor function(s) of BRCA2.METHODS:
Here, we evaluated the performance of the mouse embryonic stem cell (mESC)-based functional assay on an extensive set of BRCA2 missense variants.RESULTS:
Whereas all 20 nonpathogenic (class 1/2) variants were able to complement the cell lethal phenotype induced by loss of endogenous mouse Brca2, only 1 out of 15 pathogenic (class 4/5) variants (p.Gly2609Asp) was able to do so. However, in this variant the major tumor suppressive activity of BRCA2, i.e., homology directed repair (HDR), was severely abrogated. Among 43 evaluated VUS (class 3), 7 were unable to complement the lethal phenotype of mouse Brca2 loss while 7 other variants displayed a more severe reduction of HDR activity than observed for class 1/ 2 variants.CONCLUSION:
The mESC-based BRCA2 functional assay can reliably determine the functional impact of VUS, distinguish between pathogenic and nonpathogenic variants, and may contribute to improved cancer risk estimation for BRCA2 VUS carriers.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Prevencao_e_fatores_de_risco
/
Hereditariedade
/
Tipos_de_cancer
/
Outros_tipos
Base de dados:
MEDLINE
Assunto principal:
Variação Genética
/
Neoplasias da Mama
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Genes BRCA2
/
Células-Tronco Embrionárias Murinas
Tipo de estudo:
Evaluation_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Genet Med
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Holanda