Journal article

Estimating risks for variants of unknown significance according to their predicted pathogenicity classes with application to BRCA1

JG Dowty, E Lee, R McKean-Cowdin, BE Henderson, L Bernstein, G Ursin, JL Hopper

Breast Cancer Research and Treatment | SPRINGER | Published : 2014

Abstract

Sequence-based testing of disease-susceptibility genes has identified many variants of unknown significance (VUSs) whose pathogenicity is unknown at the time of their measurement. Female breast cancer cases aged 20-49 years at diagnosis and who have VUSs in BRCA1 and no mutations in BRCA2 have previously been identified through the population-based Los Angeles County Cancer Surveillance Program. These nominal BRCA1 VUSs have been classified as "low," "medium," and "high" risk by four classification methods: Align-GVGD, Polyphen, Grantham matrix scores, and sequence conservation in mammalian species. Average hazard ratios (HRs) for classes of variants, i.e., the age-specific incidences of can..

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Grants

Awarded by National Cancer Institute, National Institutes of Health


Awarded by California Breast Cancer Research Program of the University of California


Awarded by National Institute of Environmental Health Sciences, National Institute of Health


Awarded by California Department of Health Services as part of the statewide cancer reporting program


Awarded by NATIONAL CANCER INSTITUTE


Awarded by NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES


Funding Acknowledgements

The authors would like to thank Sean V. Tavtigian for his insightful comments and for his help with Align-GVGD. The authors are also very grateful to the women who participated in this study, the interviewers who collected the data, the phlebotomists who collected the blood samples, and Ms. Juliana Bamrick who managed all study activities. This study was supported by grants CA17054 and CA74847 from the National Cancer Institute, National Institutes of Health, by 4 PB-0092 from the California Breast Cancer Research Program of the University of California, and in part through contract number N01-PC-35139 and T32 ES-013678 from the National Institute of Environmental Health Sciences, National Institute of Health. The collection of cancer incidence data used in this publication was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885.