TY - JOUR
T1 - Integrated evaluation of DNA sequence variants of unknown clinical significance
T2 - Application to BRCA1 and BRCA2
AU - Goldgar, David E.
AU - Easton, Douglas F.
AU - Deffenbaugh, Amie M.
AU - Monteiro, Alvaro N.A.
AU - Tavtigian, Sean V.
AU - Couch, Fergus J.
N1 - Funding Information:
Members of the BIC Steering Committee are (in alphabetical order) Merete Bjørnslett (Department of Cancer Genetics, Norwegian Radium Hospital, Oslo), Larry Brody (National Human Genome Research Institute, Bethesda), Georgia Chenevix-Trench (Queensland Institute of Medical Research, Brisbane, Australia), Fergus J. Couch (Mayo Clinic College of Medicine, Rochester, MN), Amie M. Deffenbaugh (Myriad Genetics Laboratories, Salt Lake City), Peter Devilee (Department of Human Genetics, Leiden University, Leiden, Netherlands), Douglas Easton (Cancer Research UK, Genetic Epidemiology Unit, Strangeways Research Laboratory, Cambridge, United Kingdom), Charis Eng (Clinical Cancer Genetics Program, Division of Human Genetics, Ohio State University, Columbus), William Foulkes (McGill University, Montreal), David Goldgar (Unit of Genetic Epidemiology, International Agency for Research on Cancer, Lyon, France), Kathi Malone (Fred Hutchinson Cancer Research Center, Seattle), Alvaro N. A. Monteiro (H. Lee Moffitt Cancer Center, Tampa, FL), Kate Nathanson (Department of Medicine, Medical Genetics, University of Pennsylvania School of Medicine, Philadelphia), Susan Neuhausen (Epidemiology Division, Department of Medicine, University of California at Irvine, Irvine), Sharon Plon (Department of Pediatrics, Baylor College of Medicine, Houston), Csilla Szabo (Lyon, France), Sean Tavtigian (Unit of Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France), and Tom Walsh (Department of Genetics, University of Washington, Seattle). This work was supported by National Institutes of Health awards CA92309 (to A.N.A.M.), CA81203 (to D.E.G.), and CA82267 (to F.J.C.). F.J.C. also acknowledges support from the Breast Cancer Research Foundation and the U.S. Army Medical Research and Materiel Command (DAMD17-1-00-0328). D.F.E. is a Principal Research Fellow of Cancer Research UK. D.F.E. and D.E.G. received support for this work from the Canadian Institutes of Health Research through the INHERIT BRCAs research program. The authors gratefully acknowledge the technical assistance of Helene Renard, Colette Bonnardel, and Yvette Granjard.
PY - 2004/10
Y1 - 2004/10
N2 - Many sequence variants in predisposition genes are of uncertain clinical significance, and classification of these variants into high- or low-risk categories is an important problem in clinical genetics. Classification of such variants can be performed by direct epidemiological observations, including cosegregation with disease in families and degree of family history of the disease, or by indirect measures, including amino acid conservation, severity of amino acid change, and evidence from functional assays. In this study, we have developed an approach to the synthesis of such evidence in a multifactorial likelihood-ratio model. We applied this model to the analysis of three unclassified variants in BRCA1 and three in BRCA2. The evidence strongly suggests that two variants (C1787S in BRCA1 and D2723H in BRCA2) are deleterious, three (R841W in BRCA1 and Y42C and P655R in BRCA2) are neutral, and one (R1699Q in BRCA1) remains of uncertain significance. These results provide a demonstration of the utility of the model.
AB - Many sequence variants in predisposition genes are of uncertain clinical significance, and classification of these variants into high- or low-risk categories is an important problem in clinical genetics. Classification of such variants can be performed by direct epidemiological observations, including cosegregation with disease in families and degree of family history of the disease, or by indirect measures, including amino acid conservation, severity of amino acid change, and evidence from functional assays. In this study, we have developed an approach to the synthesis of such evidence in a multifactorial likelihood-ratio model. We applied this model to the analysis of three unclassified variants in BRCA1 and three in BRCA2. The evidence strongly suggests that two variants (C1787S in BRCA1 and D2723H in BRCA2) are deleterious, three (R841W in BRCA1 and Y42C and P655R in BRCA2) are neutral, and one (R1699Q in BRCA1) remains of uncertain significance. These results provide a demonstration of the utility of the model.
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U2 - 10.1086/424388
DO - 10.1086/424388
M3 - Article
C2 - 15290653
AN - SCOPUS:4544336084
SN - 0002-9297
VL - 75
SP - 535
EP - 544
JO - American journal of human genetics
JF - American journal of human genetics
IS - 4
ER -