A Systematic Genetic Assessment of 1,433 Sequence Variants of Unknown Clinical Significance in the BRCA1 and BRCA2 Breast Cancer–Predisposition Genes
Open accessAbstract
Mutation screening of the breast and ovarian cancer-predisposition genes BRCA1 and BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare nontruncating sequence variants in these genes is problematic, because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. Using data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests, we assessed the clinical significance of 1,433 sequence variants of unknown significance (VUSs) in the BRCA genes. Three independent measures were employed in the assessment: co-occurrence in trans of a VUS with known deleterious mutations; detailed analysis, by logistic regression, of personal and family history of cancer in VUS-carrying probands; and, in a subset of probands, an analysis of cosegregation with disease in pedigrees. For each of these factors, a likelihood ratio was computed under the hypothesis that the VUSs were equivalent to an "average" deleterious mutation, compared with neutral, with respect to risk. The likelihood ratios derived from each component were combined to provide an overall assessment for each VUS. A total of 133 VUSs had odds of at least 100 : 1 in favor of neutrality with respect to risk, whereas 43 had odds of at least 20 : 1 in favor of being deleterious. VUSs with evidence in favor of causality were those that were predicted to affect splicing, fell at positions that are highly conserved among BRCA orthologs, and were more likely to be located in specific domains of the proteins. In addition to their utility for improved genetics counseling of patients and their families, the global assessment reported here will be invaluable for validation of functional assays, structural models, and in silico analyses.
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Numerous chronic conditions have familial analogs caused by rare variants, including atherosclerosis through hypercholesterolemia, MODY, and BRCA1/BRCA2 breast cancer susceptibility.
“well-known examples include rare variants promoting atherosclerosis through hypercholesterolemia39, the lesions responsible for Maturity Onset Diabetes of the Young (MODY)40, and the BRCA1 and BRCA2 breast cancer susceptibility mutations41.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [41]
The identification of multiple rare variants within the same gene in largely monogenic disorders suggests that rare variants might also influence common complex traits and diseases.
“Third, the identification of multiple rare variants within the same gene contributing to largely monogenic disorders such as Cystic Fibrosis and BRCA1 and BRCA2-associated breast cancer18, 19 suggests that rare variants might also influence common complex traits and diseases.”
From Statistical analysis strategies for association studies involving rare variants (2010) · cites this paper as [19]
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- Authors
- Easton, D. F., Deffenbaugh, A. M., Pruss, D., Frye, C., Wenstrup, R. J., Allen-Brady, K., Tavtigian, S. V., Monteiro, A. N. A., Iversen, E. S., Couch, F. J., & Goldgar, D. E.
- Affiliations
- University of Cambridge (GB)
- University of Utah (US)
- Duke University (US)
- Mayo Clinic (US)
- Corresponding author
- Goldgar, David E.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2007-11
- Volume
- 81
- Issue
- 5
- Pages
- 873-883
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2265654
- OpenAlex
- W2027605814
- Cited by
- 455
- References
- 39
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 8 · 2023: 12 · 2022: 25 · 2021: 24 · 2020: 21 · 2019: 20 · 2018: 28 · 2017: 22 · 2016: 23 · 2015: 28 · 2014: 34 · 2013: 33 · 2012: 31
- FWCI
- 16.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA092309, CA92309, P50CA116201)
- 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
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- BRCA1, BRCA2, breast cancer predisposition, ovarian cancer predisposition, likelihood ratios, co-segregation analysis, family history of cancer, splicing, protein conservation, genetic counseling, mutation detection
- MeSH terms
- Adult, Aged, Breast Neoplasms, Female, Humans, Male, Middle Aged, Mutation, Likelihood Functions, Odds Ratio, Sequence Analysis, DNA, BRCA1 Protein, Genetic Predisposition to Disease, BRCA2 Protein
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