A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes

被引:347
作者
Easton, Douglas F.
Deffenbaugh, Amie M.
Pruss, Dmitry
Frye, Cynthia
Wenstrup, Richard J.
Allen-Brady, Kristina
Tavtigian, Sean V.
Monteiro, Alvaro N. A.
Iversen, Edwin S.
Couch, Fergus J.
Goldgar, David E.
机构
[1] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT 84132 USA
[2] Univ Cambridge, Strangeways Res Labs, Genet Epidemiol Unit, Cambridge, England
[3] Univ Utah, Sch Med, Myriad Genet Labs, Salt Lake City, UT 84132 USA
[4] Univ Utah, Sch Med, Dept Biomed Informat, Salt Lake City, UT 84132 USA
[5] Int Agcy Res Canc, Genet Canc Suscepitibil Grp, F-69372 Lyon, France
[6] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA
[7] Duke Univ, Inst Stat & Decis Sci, Durham, NC 27706 USA
[8] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA
关键词
MISSENSE VARIANTS; TRANSCRIPTIONAL ACTIVATION; EMBRYONIC LETHALITY; FAMILIAL BREAST; RISK ASSESSMENT; MUTATIONS; CLASSIFICATION; ALLELE;
D O I
10.1086/521032
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:873 / 883
页数:11
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