title: Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.
abstract: Sequencing tests assaying panels of genes or whole exomes are widely available for cancer risk evaluation. However, methods for classification of variants resulting from this testing are not well studied. We evaluated the ability of a variant-classification methodology based on American College of Medical Genetics and Genomics (ACMG) guidelines to define the rate of mutations and variants of uncertain significance (VUS) in 180 medically relevant genes, including all ACMG-designated reportable cancer and non-cancer-associated genes, in individuals who met guidelines for hereditary cancer risk evaluation. We performed whole-exome sequencing in 404 individuals in 253 families and classified 1,640 variants. Potentially clinically actionable (likely pathogenic [LP] or pathogenic [P]) versus nonactionable (VUS, likely benign, or benign) calls were 95% concordant with locus-specific databases and Clinvar. LP or P mutations were identified in 12 of 25 breast cancer susceptibility genes in 26 families without identified BRCA1/2 mutations (11%). Evaluation of 84 additional genes associated with autosomal-dominant cancer susceptibility identified LP or P mutations in only two additional families (0.8%). However, individuals from 10 of 253 families (3.9%) had incidental LP or P mutations in 32 non-cancer-associated genes, and 9% of individuals were monoallelic carriers of a rare LP or P mutation in 39 genes associated with autosomal-recessive cancer susceptibility. Furthermore, 95% of individuals had at least one VUS. In summary, these data support the clinical utility of ACMG variant-classification guidelines. Additionally, evaluation of extended panels of cancer-associated genes in breast/ovarian cancer families leads to only an incremental clinical benefit but substantially increases the complexity of the results.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kara N
authors.initials: KN
authors.lastname: Maxwell
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Hart
authors.affiliation: Department of Medicine, Clinical Genetics Research Lab and Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Vijai
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Kasmintan A
authors.initials: KA
authors.lastname: Schrader
authors.affiliation: Department of Medical Oncology, Division of Clinical Cancer Genetics, City of Hope, Duarte, CA 91010, USA; Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Slavin
authors.affiliation: Department of Medicine, Clinical Genetics Research Lab and Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Tinu
authors.initials: T
authors.lastname: Thomas
authors.affiliation: Department of Medicine, Division of Translational Medicine and Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Wubbenhorst
authors.affiliation: Department of Medicine, Clinical Genetics Research Lab and Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Vignesh
authors.initials: V
authors.lastname: Ravichandran
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Moore
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Chunling
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Guidugli
authors.affiliation: Department of Medicine, Division of Translational Medicine and Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Wenz
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Domchek
authors.affiliation: Department of Medicine, Clinical Genetics Research Lab and Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Robson
authors.affiliation: National Human Genetics Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Csilla
authors.initials: C
authors.lastname: Szabo
authors.affiliation: Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Neuhausen
authors.affiliation: Department of Medical Oncology, Division of Clinical Cancer Genetics, City of Hope, Duarte, CA 91010, USA; Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weitzel
authors.affiliation: Department of Medicine, Clinical Genetics Research Lab and Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Department of Medicine, Division of Translational Medicine and Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104. Electronic address: knathans@exchange.upenn.edu.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000592:standards*; D014644:Genetic Variation; D023281:Genomics / Q000592:standards*; D017408:Guidelines as Topic; D059014:High-Throughput Nucleotide Sequencing / Q000592:standards; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000592:standards*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor