title: Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic.
abstract: Despite the potential of whole-genome sequencing (WGS) to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those withBRCA1/2mutations (n = 176) and those without (n = 82). Initial analysis of potentially pathogenic variants (PPVs, defined as nonsynonymous variants with allele frequency < 1% in ESP6500) in 163 clinically-relevant genes suggested that WGS will provide useful clinical results. This is despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS). Furthermore, previously reported pathogenic missense variants did not always associate with their predicted diseases in our patients. This suggests that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants. While loss-of-function (LoF) variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with knownBRCA1/2mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes. These data illustrate how WGS can be used to improve our ability to discover patients' cancer genetic risks.
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas TX, 75390, USA.
authors.forename: Samantha B
authors.initials: SB
authors.lastname: Foley
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA ; Department of Pediatrics, McDermott Center for Human Growth and Development, and Department of Orthopaedic Surgery, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Rios
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas TX, 75390, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Mgbemena
authors.affiliation: Department of Cancer Genetics, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Robinson
authors.affiliation: Department of Human Genetics, Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Hampel
authors.affiliation: Department of Human Genetics, Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Toland
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas TX, 75390, USA ; Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Durham
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas TX, 75390, USA ; Department of Cancer Genetics, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
authors.forename: Theodora S
authors.initials: TS
authors.lastname: Ross
keywords: BRCA1/2; Cancer genetics; ClinVar; Pathogenic variants; Single nucleotide variant; Whole-genome sequence