Truncating mutations comprise the largest proportion of mutation types identifiable with sequencing. All truncating mutations are associated with loss of gene function and clinical expression of breast and ovarian cancer, with the exception of those that prematurely terminate the protein product of BRCA1 less than 10 amino acids from the C-terminus or the protein product of BRCA2 less than 110 amino acids from the C-terminus. The major problems in interpretation of the clinical significance of sequence variations apply to missense variants and intronic mutations, chain-terminating mutations that truncate BRCA1 and BRCA2 distal to amino acid positions 1853 and 3308, respectively, and mutations that eliminate the normal stop codons for these proteins.
Frank et al. described the largest study of BRCA1 and BRCA2 genetic testing results and clinical characteristics, for consecutive tests on 10,000 individuals.16 One or more variants of uncertain clinical significance in the absence of deleterious mutations were observed in 970 (13%) of the 7461 individuals sequenced in this study.16 Epidemiological and biological criteria can be applied to distinguish functional from benign variants with some success.54 For example, the prevalence of each variant in a control population, cosegregation of the variant with cancer within families, location of the variant within the gene, functional assays, demonstration of abnormal mRNA transcript processing, type of the amino acid substitution, and degree of conservation among species55 provide clues as to whether the mutation is deleterious.16 Variant BRCA test results pose a commonly encountered and highly problematic issue,56 which can possibly lead to the inappropriate use of medical interventions such as prophylactic surgery;57 thus having genetic counseling and competent test interpretation is paramount.
It should be pointed out that false-positive results (as reflected by specificities <100%) pose the most potential harm since "positive" results are used to make decisions about prophylactic breast and ovarian surgery, which are irreversible decisions. False-negative results are far more common but are dealt with by reverting to pedigree information and maintaining a high level of suspicion where indicated.
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