From a variant of unknown significance to pathogenic: Reclassification of a large novel duplication in BRCA2 by high-throughput sequencing.
Mol Genet Genomic Med
; 8(9): e1045, 2020 09.
Article
em En
| MEDLINE
| ID: mdl-31724318
ABSTRACT
BACKGROUND:
Germline mutations in BRCA1/2 significantly contribute to hereditary breast and/or ovarian cancer. Here, we report a novel BRCA2 duplication of exons 22-24 in a female patient with bilateral breast cancer at age 35 and 44. The duplicated region was initially detected by gene panel sequencing and multiplex ligation-dependent probe amplification. However, the location and orientation of the duplicated region was unknown. Therefore, it was initially classified as a variant of unknown significance.METHODS:
The spatial directional characterization of the BRCA2 duplication was achieved by targeted enrichment of the whole-genomic BRCA2 locus including exons and introns, and subsequent high-throughput sequencing. Subsequently, bioinformatics tools and a breakpoint-spanning PCR were used for identification of location and orientation of the duplication.RESULTS:
The duplicated region was arranged in tandem and direct orientation (Chr13(GRCh37)g.32951579_32960394dup; NM_000059.3 c.8754 + 651_9256+6112dup p.(Ala3088Phefs*3)). It is predicted to result in a frameshift and a premature stop codon likely triggering nonsense-mediated mRNA decay. Consequently, it is regarded as pathogenic.CONCLUSION:
This case study demonstrates that a comprehensive characterization of a structural variant by breakpoint assessment is crucial for its correct classification. Therefore, sequencing strategies including non-coding regions might be necessary to identify cancer predispositions in affected families.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Duplicação Gênica
/
Proteína BRCA2
/
Síndrome Hereditária de Câncer de Mama e Ovário
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Female
/
Humans
Idioma:
En
Revista:
Mol Genet Genomic Med
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Alemanha