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Journal of Clinical Oncology, Vol 26, No 25 (September 1), 2008: pp. 4214-4215 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.18.2667
In ReplyIstituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy
Department of Biology, University of Padua, Padua, Italy The correspondence by Giannini et al gives us the opportunity to highlight a few important points with respect to the investigation of the clinical relevance of BRCA1 sequence variants of undefined significance. They report on a novel BRCA1 variant located near the Val1688del described in our publication.1 In particular, they claim (1) the description of an approach that allowed them to classify the H1686Q as a pathogenic mutation and (2) the identification of two motifs (THV and RTLK) that might represent potential targets for missense mutations. Starting with the second claim, the intense investigation on the BRCT domains of BRCA1 as well as other proteins has left little doubt about the functional relevance of this protein structure, which is involved in phosphorylation-dependent, protein-protein interactions linked to cell cycle checkpoints and DNA repair functions.2 More specifically, the RTLK motif contains amino acid residues that are crucial for the formation of the central phosphoserine and phenylalanine binding pockets of the BRCT.2 The THV motif was recently shown to be part of an additional binding site predicted by Karchin et al3 on the opposite face from the first phosphopeptide binding cleft. Not surprisingly, because of their critical functions, both motifs are strongly conserved among BRCA1 orthologs and paralogs with at least six different unclassified variants located in these domains, most of which have already been shown to negatively affect the function of the protein.3,4 Concerning the BRCA1 H1686Q variant, several observations are reported by Giannini et al in favor of a pathogenic role of this amino acid change, which is also supported by previous functional tests. However, although extremely probable, the evidence that H1686Q represents a pathogenic mutation is not translated into a probability score. This raises a more general reasoning for the need of a standardized approach for the assessment of disease causality that must result in more homogeneous data that can be easily and readily interpreted by the professionals who are responsible for clinical management of at-risk families. Indeed, in cases like this, the clinician and/or genetic counselor is left with the difficult task of interpreting and evaluating each different type of evidence or, alternatively, blindly trusting researchers’ suspicions. In the characterization of BRCA1 Val1688del, we used the multifactorial likelihood approach, recently developed by Goldgar et al,5 which has the advantage of taking into account many data derived from independent sources to derive a final likelihood in favor of or against causality. The multifactorial likelihood approach is also particularly advantageous for those variants that do not recur in the population and for which only a few carriers are available to study. The method aims at the definition of the pathogenicity or neutrality of sequence variants based on the presence or absence of features that discriminate clearly pathogenic mutations from neutral variants and involving evolutionary conservation, co-occurrence with pathogenic mutations, and cosegregation with disease- and tumor-specific features. As such, the approach can be implemented as new gene-specific characteristics are identified.6 Most importantly, it provides the unique opportunity to rely on a standardized method to weigh independent evidence for a given variant and to give a result directly reflecting the probability of the variant to be clinically relevant. Probability thresholds of more than 1,000:1 or less than 1:100 have also been proposed to infer the pathogenicity or neutrality of a variant, respectively.5 On this specific point, it should be noted that robustness and reliability of the approach are strongly dependent on the specificity and appropriateness of gene-specific characteristics. For instance, the use of loss of heterozygosity and tumor histopathology signatures implicitly assumes that no differences between missense versus protein-truncating mutations exist, which is likely but has yet to be formally proven. Slight biases on these parameters might also derive from the selection of samples used to derive the likelihood ratios. On the contrary, analysis of cosegregation of the variant with the disease through generations provides more robust and independent confidence. Therefore, taking into account potential minor biases, the largest distances from cutoff values should be sought for a high level of confidence in variant classification. In conclusion, the study of the pathogenic role of BRCA1/2 variants remains a top priority for management of 10% to 15% of high-risk breast and ovarian cancer families who remain uninformative as a result of the identification of a variant of unclear significance. An effort should be made by the scientific community working on this subject to interpret and translate the abundant scientific evidence derived from multidisciplinary approaches, including functional and genetic-based studies, into unambiguous messages to assist genetic counselors in risk assessment and guide clinicians in making decisions on preventive and therapeutic measures. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Malacrida S, Agata S, Callegaro M, et al: BRCA1 p.Val1688del is a deleterious mutation that recurs in breast and ovarian cancer families from Northeast Italy. J Clin Oncol 26:26-31, 2008 2. Glover JN, Williams RS, Lee MS: Interactions between BRCT repeats and phosphoproteins: Tangled up in two. Trends Biochem Sci 29:579-585, 2004[CrossRef][Medline] 3. Karchin R, Monteiro AN, Tavtigian SV, et al: Functional impact of missense variants in BRCA1 predicted by supervised learning. PLoS Comput Biol 3:e26, 2007[CrossRef][Medline] 4. Carvalho MA, Marsillac SM, Karchin R, et al: Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis. Cancer Res 67:1494-1501, 2007 5. Goldgar DE, Easton DF, Deffenbaugh AM, et al: Integrated evaluation of DNA sequence variants of unknown clinical significance: Application to BRCA1 and BRCA2. Am J Hum Genet 75:535-544, 2004[CrossRef][Medline] 6. Spurdle AB, Lakhani SR, Healey S, et al: Clinical classification of BRCA1 and BRCA2 DNA sequence variants: The value of cytokeratin profiles and evolutionary analysis—A report from the kConFab Investigators. J Clin Oncol 26:1657-1663, 2008
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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