Accurate classification of BRCA1 variants with saturation genome editing

Gregory M. Findlay, Riza M. Daza, Beth Martin, Melissa D. Zhang, Anh P. Leith, Molly Gasperini, Joseph D. Janizek, Xingfan Huang, Lea M. Starita () and Jay Shendure ()
Additional contact information
Gregory M. Findlay: University of Washington
Riza M. Daza: University of Washington
Beth Martin: University of Washington
Melissa D. Zhang: University of Washington
Anh P. Leith: University of Washington
Molly Gasperini: University of Washington
Joseph D. Janizek: University of Washington
Xingfan Huang: University of Washington
Lea M. Starita: University of Washington
Jay Shendure: University of Washington

Nature, 2018, vol. 562, issue 7726, 217-222

Abstract: 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.

Keywords: BRCA2 Variants; Missense SNVs; Single Nucleotide Variants (SNVs); Cell Happens; Synonymous SNVs (search for similar items in EconPapers)
Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (11)

Downloads: (external link)
https://www.nature.com/articles/s41586-018-0461-z Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:562:y:2018:i:7726:d:10.1038_s41586-018-0461-z

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-018-0461-z

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().