BRCA1 Saturation Genome Editing Function Scores

Academic License Agreement

The University of Washington hereby allows User and Institution to search, download, copy or use BRCA1 Saturation Genome Editing function scores (“BRCA1 SGE scores”) on the following conditions:

1. The scores are being made available here for non-profit, non-commercial uses only. If User wishes to use BRCA1 SGE scores, derivatives of BRCA1 SGE scores, or the data on which they are based, for any commercial or for-profit purpose, please contact the corresponding authors. Low-cost or no-cost licenses will be extended for commercial or for-profit uses, contingent on the engagement of the licensing entity in best practices specified by ClinGen for BRCA1 variant data sharing.

2. The University of Washington owns the intellectual property for BRCA1 SGE scores. In any reposting of the scores or their derivatives, User agrees to retain the copyright, trademark, or other notices pertaining to BRCA1 SGE scores as provided by UW associated with the BRCA1 SGE scores. Use of the copyright in any printed excerpts shall include the following notice (or the equivalent thereof): 'BRCA1 SGE scores are the copyright of the University of Washington.'

3. Any risk associated with using BRCA1 SGE scores by User is with User and Institution. BRCA1 SGE scores are experimental in nature and is made available as a research courtesy 'AS IS,' without obligation by the University of Washington to provide accompanying services or support. The BRCA1 SGE scores are for informational purposes only, and is not intended to be a substitute for professional medical advice, diagnosis, or treatment. UW AND THE DEVELOPER EXPRESSLY DISCLAIM ANY AND ALL WARRANTIES REGARDING THE BRCA1 SGE scores, WHETHER EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO WARRANTIES PERTAINING TO NON-INFRINGEMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE.

4. BRCA1 SGE scores may be accessed after providing the following information:



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Saturation Genome Editing (SGE) is a CRISPR/Cas9-based method to functionally test the effects of large numbers of variants in their native genomic context ( Findlay et al. Nature 2014 ). For SGE of BRCA1 , we developed an assay in a haploid human cell line (HAP1) in which BRCA1 is essential ( Blomen et al. Science 2015 ). In each SGE experiment, nearly all possible single nucleotide variants (SNVs) over a ~100 bp region of BRCA1 are introduced via multiplex homology-directed repair, such that each cell acquires a single variant in the targeted exon. Because BRCA1 is essential in this cell line, incorporation of SNVs that cause loss of BRCA1 function are depleted from the population of cells over time, an effect quantified with massively parallel DNA sequencing.

Function scores are reported here for 3,893 SNVs located within or near the thirteen exons that encode for the RING and BRCT domains of BRCA1 (exons 2-5 and 15-23, respectively). Function scores quantify the depletion of SNVs, and are log2-scaled such that the median synonymous SNV scores as 0. More negative function scores are indicative of loss-of-function variants; the median nonsense SNV scored -2.12. Each SNV was placed into one of three broad functional classes based on its function score: 'functional'/'FUNC' (score > -0.748, 72.5%), 'intermediate'/'INT' ( -0.748 > score > -1.328, 6.4%), and 'non-functional'/'LOF' (score < -1.328, 21.1%).

Targeted RNA sequencing was performed to assess how each exonic SNV impacts BRCA1 mRNA levels. RNA scores are log2-based ratios reporting how depleted each SNV is in mRNA (relative to the median synonymous SNV in each experiment).

For more details and/or to cite these scores, please refer to the following manuscript:

Findlay, G.M., Daza, R.M., Martin, B., Zhang, M.D., Leith, A.P., Gasperini, M., Janizek, J.D., Huang, X., Starita, L.M., Shendure, J. Accurate classification of BRCA1 variants with saturation genome editing. Nature (2018). https://doi.org/10.1038/s41586-018-0461-z.


SGE function scores and data are the copyright of the University of Washington and subject to the terms of the licensing agreement.


SGE function scores and data are the copyright of the University of Washington and subject to the terms of the licensing agreement.

Citation:

Findlay, G.M., Daza, R.M., Martin, B., Zhang, M.D., Leith, A.P., Gasperini, M., Janizek, J.D., Huang, X., Starita, L.M., Shendure, J. Accurate classification of BRCA1 variants with saturation genome editing. Nature (2018). https://doi.org/10.1038/s41586-018-0461-z.


For more information, please visit:

Brotman Baty Institute

Shendure Lab