Sensitivity of BRCA1/2 testing in high-risk breast/ovarian/male breast cancer families: little contribution of comprehensive RNA/NGS panel testing
van Veen, E
Newman, William G
Evans, D Gareth R
AffiliationGenomic Medicine, Institute of Human Development, St. Mary's Hospital, Manchester Academic Health Science Centre, Central Manchester Foundation Trust, University of Manchester, Manchester
MetadataShow full item record
AbstractThe sensitivity of testing BRCA1 and BRCA2 remains unresolved as the frequency of deep intronic splicing variants has not been defined in high-risk familial breast/ovarian cancer families. This variant category is reported at significant frequency in other tumour predisposition genes, including NF1 and MSH2. We carried out comprehensive whole gene RNA analysis on 45 high-risk breast/ovary and male breast cancer families with no identified pathogenic variant on exonic sequencing and copy number analysis of BRCA1/2. In addition, we undertook variant screening of a 10-gene high/moderate risk breast/ovarian cancer panel by next-generation sequencing. DNA testing identified the causative variant in 50/56 (89%) breast/ovarian/male breast cancer families with Manchester scores of ≥50 with two variants being confirmed to affect splicing on RNA analysis. RNA sequencing of BRCA1/BRCA2 on 45 individuals from high-risk families identified no deep intronic variants and did not suggest loss of RNA expression as a cause of lost sensitivity. Panel testing in 42 samples identified a known RAD51D variant, a high-risk ATM variant in another breast ovary family and a truncating CHEK2 mutation. Current exonic sequencing and copy number analysis variant detection methods of BRCA1/2 have high sensitivity in high-risk breast/ovarian cancer families. Sequence analysis of RNA does not identify any variants undetected by current analysis of BRCA1/2. However, RNA analysis clarified the pathogenicity of variants of unknown significance detected by current methods. The low diagnostic uplift achieved through sequence analysis of the other known breast/ovarian cancer susceptibility genes indicates that further high-risk genes remain to be identified.European Journal of Human Genetics advance online publication, 8 June 2016; doi:10.1038/ejhg.2016.57.
CitationSensitivity of BRCA1/2 testing in high-risk breast/ovarian/male breast cancer families: little contribution of comprehensive RNA/NGS panel testing. 2016: Eur J Hum Genet
JournalEuropean Journal of Human Genetics
- Implementation of next-generation sequencing for molecular diagnosis of hereditary breast and ovarian cancer highlights its genetic heterogeneity.
- Authors: Pinto P, Paulo P, Santos C, Rocha P, Pinto C, Veiga I, Pinheiro M, Peixoto A, Teixeira MR
- Issue date: 2016 Sep
- Statewide Retrospective Review of Familial Pancreatic Cancer in Delaware, and Frequency of Genetic Mutations in Pancreatic Cancer Kindreds.
- Authors: Catts ZA, Baig MK, Milewski B, Keywan C, Guarino M, Petrelli N
- Issue date: 2016 May
- Screening of <i>BRCA1/2</i> deep intronic regions by targeted gene sequencing identifies the first germline <i>BRCA1</i> variant causing pseudoexon activation in a patient with breast/ovarian cancer.
- Authors: Montalban G, Bonache S, Moles-Fernández A, Gisbert-Beamud A, Tenés A, Bach V, Carrasco E, López-Fernández A, Stjepanovic N, Balmaña J, Diez O, Gutiérrez-Enríquez S
- Issue date: 2019 Feb
- Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2.
- Authors: Kraus C, Hoyer J, Vasileiou G, Wunderle M, Lux MP, Fasching PA, Krumbiegel M, Uebe S, Reuter M, Beckmann MW, Reis A
- Issue date: 2017 Jan 1
- The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants.
- Authors: Schubert S, van Luttikhuizen JL, Auber B, Schmidt G, Hofmann W, Penkert J, Davenport CF, Hille-Betz U, Wendeburg L, Bublitz J, Tauscher M, Hackmann K, Schröck E, Scholz C, Wallaschek H, Schlegelberger B, Illig T, Steinemann D
- Issue date: 2019 Jun 1