Deciphering the Clinical Significance of BRCA Variants

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Title: Deciphering the Clinical Significance of BRCA Variants
Creators: Spearman, Andrew
Advisor: Toland, Amanda
Issue Date: 2008-06
Abstract: The identification of genes predisposing individuals for specific diseases has increased the value of genetic testing. Two genes, BRCA1 and BRCA2, have been shown to be significant in hereditary breast and ovarian cancers. Unfortunately, the mutation results of BRCA genetic testing are sometimes unclear. A class of mutations, termed “variants of uncertain significance” (VUS), provides inconclusive and unhelpful results in genetic testing because it is unknown whether these variants are cancer causing mutations or neutral polymorphisms. In our study, we combined independent variables including tumor loss of heterozygosity, co-occurrence with a known deleterious mutation in trans, sequence conservation or splice site analysis, pathological data (estrogen receptor, progesterone receptor, and Her2Neu status; tumor grade; and tumor histology), and personal cancer history (age of onset and cancer type) to try to classify VUS as deleterious or neutral. This selection of data allows one to assess the pathogenicity of VUS without segregation analysis or familial information, which is often unavailable because of family absence or unwillingness to undergo genetic testing. With these independent data sources, we used a modified multifactorial approach for each variant to calculate a final likelihood score. We were able to utilize our method with 98% sensitivity and 76% specificity on 57 tumor samples from 44 known deleterious variants. Additionally, we evaluated 56 tumor samples from 54 unique classified and unclassified variants. Among the 33 unclassified VUS, we quantified 21 as neutral. The classification of VUS as deleterious or neutral will aid patient care, specifically improving future decision making regarding screening, chemoprevention, prophylactic treatment, and familial risk.
Embargo: A one-year embargo was granted for this item.
Series/Report no.: The Ohio State University. College of Biological Sciences Honors Theses; 2008
Keywords: BRCA1
Variants of Uncertain Significance
genetic testing
Sponsors: Mayers Summer Research Fellowship
Arts and Sciences Undergraduate Research Scholarship
The Ohio State University Comprehensive Cancer Center
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Attribution-NonCommercial-NoDerivs 3.0 Unported