Reclassification of BRCA1 and BRCA2 variants of uncertain significance: a multifactorial analysis of multicentre prospective cohort.
J Med Genet
; 55(12): 794-802, 2018 12.
Article
en En
| MEDLINE
| ID: mdl-30415210
ABSTRACT
BACKGROUND:
BRCA1 and BRCA2 (BRCA1/2) variants classified ambiguously as variants of uncertain significance (VUS) are a major challenge for clinical genetic testing in breast cancer; their relevance to the cancer risk is unclear and the association with the response to specific BRCA1/2-targeted agents is uncertain. To minimise the proportion of VUS in BRCA1/2, we performed the multifactorial likelihood analysis and validated this method using an independent cohort of patients with breast cancer.METHODS:
We used a data set of 2115 patients with breast cancer from the nationwide multicentre prospective Korean Hereditary Breast Cancer study. In total, 83 BRCA1/2 VUSs (BRCA1, n=26; BRCA2, n=57) were analysed. The multifactorial probability was estimated by combining the prior probability with the overall likelihood ratio derived from co-occurrence of each VUS with pathogenic variants, personal and family history, and tumour characteristics. The classification was compared with the interpretation according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG/AMP) guidelines. An external validation was conducted using independent data set of 810 patients.RESULTS:
We were able to redefine 38 VUSs (BRCA1, n=10; BRCA2, n=28). The revised classification was highly correlated with the ACMG/AMP guideline-based interpretation (BRCA1, p for trend=0.015; BRCA2, p=0.001). Our approach reduced the proportion of VUS from 19% (154/810) to 8.9% (72/810) in the retrospective validation data set.CONCLUSION:
The classification in this study would minimise the 'uncertainty' in clinical interpretation, and this validated multifactorial model can be used for the reliable annotation of BRCA1/2 VUSs.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Variación Genética
/
Proteína BRCA1
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Predisposición Genética a la Enfermedad
/
Proteína BRCA2
/
Estudios de Asociación Genética
Tipo de estudio:
Clinical_trials
/
Diagnostic_studies
/
Guideline
/
Observational_studies
/
Prognostic_studies
Límite:
Female
/
Humans
País/Región como asunto:
Asia
Idioma:
En
Revista:
J Med Genet
Año:
2018
Tipo del documento:
Article