Findlay_2018.yml

title: BRCA1 Saturation Genome Editing
abstract: >-
  Variants of uncertain significance fundamentally limit the clinical utility of genetic information. The challenge 
  they pose is epitomized by BRCA1, a tumour suppressor gene in which germline loss-of-function variants predispose 
  women to breast and ovarian cancer. Although BRCA1 has been sequenced in millions of women, the risk associated with 
  most newly observed variants cannot be definitively assigned. Here we use saturation genome editing to assay 96.5% of 
  all possible single-nucleotide variants (SNVs) in 13 exons that encode functionally critical domains of BRCA1. 
  Functional effects for nearly 4,000 SNVs are bimodally distributed and almost perfectly concordant with established 
  assessments of pathogenicity. Over 400 non-functional missense SNVs are identified, as well as around 300 SNVs that 
  disrupt expression. We predict that these results will be immediately useful for the clinical interpretation of BRCA1 
  variants, and that this approach can be extended to overcome the challenge of variants of uncertain significance in 
  additional clinically actionable genes.
document:
  title: Accurate classification of BRCA1 variants with saturation genome editing
  system:
    Nature
  date: "2018-09-12"
  ref: https://doi.org/10.1038/s41586-018-0461-z
datasets:
  - system: MaveDB
    accession: urn:mavedb:00000097
    ref: https://mavedb.org/#/experiment-sets/urn:mavedb:00000097
    description: processed scores, including scores for each replicate of each exon
  - system: GEO
    accession: GSE117159
    ref: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE117159
    description: raw sequencing data
  - system: website
    accession: https://sge.gs.washington.edu/BRCA1/
    ref: https://sge.gs.washington.edu/BRCA1/
    description: processed scores and visualizations hosted by the investigators
variantLibrary:
  scope:
    type: coding
  targetSequences:
    - id: NM_007294.3
      sequenceAlphabet: DNA
  generationMethod:
    type: endogenous locus library
    system: SpCas9
    mechanism: nuclease
    description: Array-synthesized oligo pools (Agilent)
  deliveryMethod:
    type: other
    description: Lipofection - TurboFectin
phenotypicAssay:
  dimensionality:
    type: combined functional data
  replication:
    type: biological
    description: two biological replicates were performed
  method:
    type: survival assessment assay
  method:
    type: bulk RNA-sequencing
  relevance:
    - system: https://www.omim.org/
      code: "604370"
      label: BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1; BROVCA1
    - system: https://www.omim.org/
      code: "113705"
      label: BRCA1 DNA REPAIR-ASSOCIATED PROTEIN; BRCA1
    - system: https://mondo.monarchinitiative.org/
      code: MONDO:0004984
      label: basal-like breast carcinoma
    - system: https://mondo.monarchinitiative.org/
      code: MONDO:0011450
      label: breast-ovarian cancer, familial, susceptibility to, 1
  modelSystem:
    type: immortalized human cells
    description: HAP1
    codings:
      - system: https://www.ncbi.nlm.nih.gov/taxonomy
        code: NCBI:txid9606
        label: Homo sapiens
  profilingStrategy: direct sequencing
  sequencingReadType: multi-segment