ArticleGenetics in medicine : official journal of the American College of Medical Genetics2014
Large numbers of individuals are required to classify and define risk for rare variants in known cancer risk genes.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Enhancing missense variant classification in predicted intrinsically disordered regions.PloS one · 2026Article
- Clinical implications of conflicting variant interpretations in the cancer genetics clinic.Genetics in medicine : official journal of the American College of Medical Genetics · 2023Article
- Modeling the impact of data sharing on variant classification.Journal of the American Medical Informatics Association : JAMIA · 2023Article
- An algorithm for optimal testing in co-segregation analysis.Human mutation · 2022Article
- Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance.Genetics in medicine : official journal of the American College of Medical Genetics · 2019Article
- Power of pedigree likelihood analysis in extended pedigrees to classify rare variants of uncertain significance in cancer risk genes.Familial cancer · 2017Article
- EXAMINING EVIDENCE IN U.S. PAYER COVERAGE POLICIES FOR MULTI-GENE PANELS AND SEQUENCING TESTS.International journal of technology assessment in health care · 2017Article
- Power to the People: Data Citizens in the Age of Precision Medicine.Vanderbilt journal of entertainment and technology law · 2017Article
- Family Studies for Classification of Variants of Uncertain Classification: Current Laboratory Clinical Practice and a New Web-Based Educational Tool.Journal of genetic counseling · 2016Article
- Family-Specific Variants and the Limits of Human Genetics.Trends in molecular medicine · 2016Review
- Barbarians at the Gate: Consumer-Driven Health Data Commons and the Transformation of Citizen Science.American journal of law & medicine · 2016Article
- The challenge of comprehensive and consistent sequence variant interpretation between clinical laboratories.Genetics in medicine : official journal of the American College of Medical Genetics · 2016Article
- Review
- The FDA and genomic tests--getting regulation right.The New England journal of medicine · 2015Article
- Pragmatic and Ethical Challenges of Incorporating the Genome into the Electronic Medical Record.Current genetic medicine reports · 2014Article
- Economic regulation of next-generation sequencing.The Journal of law, medicine & ethics : a journal of the American Society of Law, Medicine & Ethics · 2014Article
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
purposeUp to half of unique genetic variants in genomic evaluations of familial cancer risk will be rare variants of uncertain significance. Classification of rare variants will be an ongoing issue as genomic testing becomes more common.
methodsWe modified standard power calculations to explore sample sizes necessary to classify and estimate relative disease risk for rare variant frequencies (0.001-0.00001) and varying relative risk (20-1.5), using population-based and family-based designs focusing on breast and colon cancer. We required 80% power and tolerated a 10% false-positive rate because variants tested will be in known genes with high pretest probability.
resultsUsing population-based strategies, hundreds to millions of cases are necessary to classify rare cancer variants. Larger samples are necessary for less frequent and less penetrant variants. Family-based strategies are robust to changes in variant frequency and require between 8 and 1,175 individuals, depending on risk.
conclusionIt is unlikely that most rare missense variants will be classifiable in the near future, and accurate relative risk estimates may never be available for very rare variants. This knowledge may alter strategies for communicating information about variants of uncertain significance to patients.
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