title: A Systematic Comparison of Traditional and Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Genes in More Than 1000 Patients.
abstract: Gene panels for hereditary breast and ovarian cancer risk assessment are gaining acceptance, even though the clinical utility of these panels is not yet fully defined. Technical questions remain, however, about the performance and clinical interpretation of gene panels in comparison with traditional tests. We tested 1105 individuals using a 29-gene next-generation sequencing panel and observed 100% analytical concordance with traditional and reference data on >750 comparable variants. These 750 variants included technically challenging classes of sequence and copy number variation that together represent a significant fraction (13.4%) of the pathogenic variants observed. For BRCA1 and BRCA2, we also compared variant interpretations in traditional reports to those produced using only non-proprietary resources and following criteria based on recent (2015) guidelines. We observed 99.8% net report concordance, albeit with a slightly higher variant of uncertain significance rate. In 4.5% of BRCA-negative cases, we uncovered pathogenic variants in other genes, which appear clinically relevant. Previously unseen variants requiring interpretation accumulated rapidly, even after 1000 individuals had been tested. We conclude that next-generation sequencing panel testing can provide results highly comparable to traditional testing and can uncover potentially actionable findings that may be otherwise missed. Challenges remain for the broad adoption of panel tests, some of which will be addressed by the accumulation of large public databases of annotated clinical variants.
authors.affiliation: Invitae, San Francisco, California. Electronic address: steve.lincoln@invitae.com.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Lincoln
authors.affiliation: Invitae, San Francisco, California.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Invitae, San Francisco, California.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Anderson
authors.affiliation: Invitae, San Francisco, California.
authors.forename: Shan
authors.initials: S
authors.lastname: Yang
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Desmond
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Mills
authors.affiliation: Invitae, San Francisco, California.
authors.forename: Geoffrey B
authors.initials: GB
authors.lastname: Nilsen
authors.affiliation: Invitae, San Francisco, California.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Jacobs
authors.affiliation: Invitae, San Francisco, California.
authors.forename: Federico A
authors.initials: FA
authors.lastname: Monzon
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Allison W
authors.initials: AW
authors.lastname: Kurian
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: James M
authors.initials: JM
authors.lastname: Ford
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
authors.forename: Leif W
authors.initials: LW
authors.lastname: Ellisen
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D052138:Genes, Neoplasm; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics*