Impact of proactive high-throughput functional assay data on BRCA1 variant interpretation in 3684 patients with breast or ovarian cancer
- 6 January 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Human Genetics
- Vol. 65 (3), 209-220
- https://doi.org/10.1038/s10038-019-0713-2
Abstract
The clinical utility of BRCA1/2 genotyping was recently extended from the selection of subjects at high risk for hereditary breast and ovary cancer to the identification of candidates for poly (ADP-ribose) polymerase (PARP) inhibitor treatment. This underscores the importance of accurate interpretation of BRCA1/2 genetic variants and of reducing the number of variants of uncertain significance (VUSs). Two recent studies by Findlay et al. and Starita et al. introduced high-throughput functional assays, and proactively analyzed variants in specific regions regardless of whether they had been previously observed. We retrospectively reviewed all BRCA1 and BRCA2 germline genetic test reports from patients with breast or ovarian cancer examined at Asan Medical Center (Seoul, Korea) between September 2011 and December 2018. Variants were assigned pathogenic or benign strong evidence codes according to the functional classification and were reclassified according to the ACMG/AMP 2015 guidelines. Among 3684 patients with available BRCA1 and BRCA2 germline genetic test reports, 429 unique variants (181 from BRCA1) were identified. Of 34 BRCA1 variants intersecting with the data reported by Findlay et al., three missense single-nucleotide variants from four patients (0.11%, 4/3684) were reclassified from VUSs to likely pathogenic variants. Four variants scored as functional were reclassified into benign or likely benign variants. Three variants that overlapped with the data reported by Starita et al. could not be reclassified. In conclusion, proactive high-throughput functional study data are useful for the reclassification of clinically observed VUSs. Integrating additional evidence, including functional assay results, may help reduce the number of VUSs.Keywords
This publication has 50 references indexed in Scilit:
- A Classification Model for BRCA2 DNA Binding Domain Missense Variants Based on Homology-Directed Repair ActivityCancer Research, 2013
- Deriving the consequences of genomic variants with the Ensembl API and SNP Effect PredictorBioinformatics, 2010
- Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA1 by Structural and Functional AssaysCancer Research, 2010
- Identification of Breast Tumor Mutations in BRCA1 That Abolish Its Function in Homologous DNA RecombinationCancer Research, 2010
- Detection of nonneutral substitution rates on mammalian phylogeniesGenome Research, 2009
- Human Splicing Finder: an online bioinformatics tool to predict splicing signalsNucleic Acids Research, 2009
- Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test resultsHuman Mutation, 2008
- Mouse embryonic stem cell–based functional assay to evaluate mutations in BRCA2Nature Medicine, 2008
- A Systematic Genetic Assessment of 1,433 Sequence Variants of Unknown Clinical Significance in the BRCA1 and BRCA2 Breast Cancer–Predisposition GenesAmerican Journal of Human Genetics, 2007
- Maximum Entropy Modeling of Short Sequence Motifs with Applications to RNA Splicing SignalsJournal of Computational Biology, 2004