Accurate classification of BRCA1 variants with saturation genome editing
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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.
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Time-course survival assays or varying doses of cellular stressor can discriminate mildly deleterious mutations causing gradual fitness decline from those with strong loss-of-function effects.
“In their simplest implementation, using a single time point, survival assays have a tendency to dichotomise outcomes; however, the use of time-course survival assays, or varying doses of cellular stressor, can discriminate mildly deleterious mutations which cause gradual fitness decline from those with strong loss-of-function effects (36).”
From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [36]
The Methods (Transfection of HAP1 cells; page unavailable) describe measuring cell survival at days 2, 5, and 7. The Results (Function scores for 3,893 BRCA1 SNVs; page unavailable) distinguish intermediate from non-functional variants. The paper does not show that time-course assays identify gradual fitness decline, or that varying cellular-stressor doses distinguish mildly deleterious from strong loss-of-function variants. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMAVEs provide a functional readout for large numbers of variants in genes of interest simultaneously, often on a scale of many thousands of variants.
“MAVEs provide a functional readout for large numbers of variants in genes of interest simultaneously, sometimes referred to as fitness landscapes (34), often on a scale of many thousands of variants (35, 36).”
From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [36]
Single-time-point survival assays tend to dichotomise outcomes.
“In their simplest implementation, using a single time point, survival assays have a tendency to dichotomise outcomes; however, the use of time-course survival assays, or varying doses of cellular stressor, can discriminate mildly deleterious mutations which cause gradual fitness decline from those with strong loss-of-function effects (36).”
From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [36]
The Methods (Transfection of HAP1 cells; page unavailable) describe survival measurements at days 2, 5 and 7, while the Results (Function scores for 3,893 BRCA1 SNVs; page unavailable) classify variants as functional, non-functional or intermediate. Neither passage says that single-time-point survival assays tend to dichotomise outcomes; searches for that comparison and for gradual fitness decline found no such statement. (LLM, conf=0.72)
Experimental — accuracy not yet measuredHighly parallelized in vitro cellular assays that assess functional effects of all variants in a disease-associated gene can transform interpretation of novel variants.
“Highly parallelized in vitro cellular assays that allow assessment of the functional effects of all variants in a disease-associated gene can transform interpretation of novel variants29”
From A brief history of human disease genetics (2020) · cites this paper as [29]
For genes harbouring medically actionable variants, such as BRCA1 and BRCA2 mutations causal for early-onset breast and ovarian cancer, functional studies can support translational interpretation of novel alleles identified by medical sequencing.
“In addition, for genes harbouring variants with medically actionable consequences (as with the BRCA1 and BRCA2 mutations that are causal for early-onset breast and ovarian cancer), functional studies can support the translational interpretation of novel alleles identified by medical sequencing29.”
From A brief history of human disease genetics (2020) · cites this paper as [29]
Hap1 cells are widely used in MAVEs.
“Also widely used in MAVEs are spontaneously haploid mammalian cells such as the myeloid lineage Hap1 line (36).”
From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [36]
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Xu, J., Aslanzadeh, V., Kudla, G., & Semple, R. K. (2026) · Journal of Molecular Endocrinology · doi:10.1530/jme-25-0134
- Authors
- 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.
- Affiliations
- University of Washington (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Starita, Lea M.
- Shendure, Jay
- ORCID
- Venue
- Nature
- Published
- 2018-09-12
- Volume
- 562
- Issue
- 7726
- Pages
- 217-222
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6181777
- OpenAlex
- W2889874867
- Cited by
- 843
- References
- 53
- Citations by year
- 2026: 96 · 2025: 100 · 2024: 110 · 2023: 116 · 2022: 95 · 2021: 107 · 2020: 115 · 2019: 81 · 2018: 20 · 2017: 1 · 2016: 1
- FWCI
- 49.53
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Human Genome Research Institute (DP1HG007811, R01HG009136)
- National Cancer Institute (F30CA213728)
- National Institute of General Medical Sciences (T32GM007266)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- BRCA1, variants of uncertain significance, saturation genome editing, CRISPR/Cas9, loss-of-function mutations, germline mutations, single nucleotide variants, breast cancer predisposition, ovarian cancer predisposition, missense mutations
- MeSH terms
- Gene Editing, Loss of Function Mutation, Cell Line, Exons, Female, Humans, Models, Molecular, Prognosis, RNA, Messenger, Genetic Variation, Genome, Human, BRCA1 Protein, Genetic Predisposition to Disease, Genes, Essential, Recombinational DNA Repair, Hereditary Breast and Ovarian Cancer Syndrome
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