title: Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol.
abstract: Next-generation sequencing in cancer research may reveal germline variants of clinical significance. We report patient preferences for return of results and the prevalence of incidental pathogenic germline variants (PGVs).
  
  
  
  Targeted exome sequencing of 202 genes was carried out in 1000 advanced cancers using tumor and normal DNA in a research laboratory. Pathogenic variants in 18 genes, recommended for return by The American College of Medical Genetics and Genomics, as well as PALB2, were considered actionable. Patient preferences of return of incidental germline results were collected. Return of results was initiated with genetic counseling and repeat CLIA testing.
  
  
  
  Of the 1000 patients who underwent sequencing, 43 had likely PGVs: APC (1), BRCA1 (11), BRCA2 (10), TP53 (10), MSH2 (1), MSH6 (4), PALB2 (2), PTEN (2), TSC2 (1), and RB1 (1). Twenty (47%) of 43 variants were previously known based on clinical genetic testing. Of the 1167 patients who consented for a germline testing protocol, 1157 (99%) desired to be informed of incidental results. Twenty-three previously unrecognized mutations identified in the research environment were confirmed with an orthogonal CLIA platform. All patients approached decided to proceed with formal genetic counseling; in all cases where formal genetic testing was carried out, the germline variant of concern validated with clinical genetic testing.
  
  
  
  In this series, 2.3% patients had previously unrecognized pathogenic germline mutations in 19 cancer-related genes. Thus, genomic sequencing must be accompanied by a plan for return of germline results, in partnership with genetic counseling.
authors.affiliation: Department of Investigational Cancer Therapeutics Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy Department of Surgical Oncology fmeric@mdanderson.org.
authors.forename: F
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy.
authors.forename: L
authors.initials: L
authors.lastname: Brusco
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine Program of Clinical Cancer Genetics.
authors.forename: M
authors.initials: M
authors.lastname: Daniels
authors.affiliation: Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy.
authors.forename: C
authors.initials: C
authors.lastname: Wathoo
authors.affiliation: Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy.
authors.forename: A M
authors.initials: AM
authors.lastname: Bailey
authors.affiliation: Program of Clinical Cancer Genetics.
authors.forename: L
authors.initials: L
authors.lastname: Strong
authors.affiliation: Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy.
authors.forename: K
authors.initials: K
authors.lastname: Shaw
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine Program of Clinical Cancer Genetics.
authors.forename: K
authors.initials: K
authors.lastname: Lu
authors.affiliation: Department of Bioinformatics and Computational Biology.
authors.forename: Y
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Bioinformatics and Computational Biology.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy Department of RedSky/Biomedical Institute of the Americas, El Paso, USA.
authors.forename: H
authors.initials: H
authors.lastname: Lara-Guerra
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: J
authors.initials: J
authors.lastname: Litton
authors.affiliation: Department of Breast Medical Oncology Program of Clinical Cancer Genetics.
authors.forename: B
authors.initials: B
authors.lastname: Arun
authors.affiliation: Department of Systems Biology.
authors.forename: A K
authors.initials: AK
authors.lastname: Eterovic
authors.affiliation: Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy.
authors.forename: U
authors.initials: U
authors.lastname: Aytac
authors.affiliation: Department of Hematopathology.
authors.forename: M
authors.initials: M
authors.lastname: Routbort
authors.affiliation: Department of Investigational Cancer Therapeutics.
authors.forename: V
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: Department of Investigational Cancer Therapeutics.
authors.forename: F
authors.initials: F
authors.lastname: Janku
authors.affiliation: Department of Systems Biology Department of Melanoma Medical Oncology.
authors.forename: M A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Department of Gastrointestinal (GI) Medical Oncology, MD Anderson Cancer Center, Houston.
authors.forename: S
authors.initials: S
authors.lastname: Kopetz
authors.affiliation: Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy Department of Genomic Medicine.
authors.forename: J
authors.initials: J
authors.lastname: Mendelsohn
authors.affiliation: Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy Department of Systems Biology.
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy Department of Bioinformatics and Computational Biology.
authors.forename: K
authors.initials: K
authors.lastname: Chen
mesh_terms: D059472:Exome / Q000235:genetics; D005817:Genetic Counseling; D018095:Germ-Line Mutation / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins
keywords: BRCA1; genetics; hereditary cancer risk; incidental results; next-generation sequencing; personalized therapy