The BRCA2 c.9004G>A (E2002K) [corrected] variant is likely pathogenic and recurs in breast and/or ovarian cancer families of French Canadian descent.
ABSTRACT Specific BRCA1 and BRCA2 mutations recur in French Canadian breast and/or ovarian cancer families because of common ancestors, facilitating carrier detection in this population. We recently reported a BRCA2 c.9004G>A variant of unknown clinical significance in two French Canadian breast cancer families. It confers a E3002K alteration in the conserved C-terminus domain of BRCA2, and has been reported in non-French Canadian cancer families. Seven variant positive French Canadian families have since been identified by mutation screening of referrals to hereditary cancer clinics. In this article, we describe the cancer phenotypes of these families and further assess the contribution of this variant in the French Canadian population. We screened index breast cancer cases from 58 cancer families with at least three confirmed cases of breast and/or ovarian cancer and 960 breast cancer cases (48 years mean age) not selected for family history of cancer that were previously found not to carry the most common BRCA1 and BRCA2 mutations reported in this population. The index variant-positive cases from each family had breast cancer between the ages of 35-55 years (43 years mean age); and reported close relatives with breast cancer diagnoses between the ages of 28-84 years (57 years mean age). Three families had ovarian or peritoneal cancers. BRCA2-associated cancers, such as bladder, esophagus, pancreas, prostate, and thyroid cancers also occurred in these families. One c.9004G>A carrier also harbored the PALB2 c.2323C>T (Q775X) mutation found to recur in French Canadian breast cancer cases. No new BRCA2 variant carriers were identified in mutation screens. The absence of BRCA2 c.9004G>A carriers in the breast cancer cases not selected for family history contrasts with familial cases, supporting a pathogenic status for this variant and addition to the existing common BRCA1 and BRCA2 mutation-screening panel for French Canadian breast and/or ovarian cancer families.
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ABSTRACT: Mutations in the BRCA2 (breast cancer susceptibility gene 2) tumor suppressor lead to chromosomal instability due to defects in the repair of double-strand DNA breaks (DSBs) by homologous recombination, but BRCA2's role in this process has been unclear. Here, we present the 3.1 angstrom crystal structure of a approximately 90-kilodalton BRCA2 domain bound to DSS1, which reveals three oligonucleotide-binding (OB) folds and a helix-turn-helix (HTH) motif. We also (i) demonstrate that this BRCA2 domain binds single-stranded DNA, (ii) present its 3.5 angstrom structure bound to oligo(dT)9, (iii) provide data that implicate the HTH motif in dsDNA binding, and (iv) show that BRCA2 stimulates RAD51-mediated recombination in vitro. These findings establish that BRCA2 functions directly in homologous recombination and provide a structural and biochemical basis for understanding the loss of recombination-mediated DSB repair in BRCA2-associated cancers.Science 10/2002; 297(5588):1837-48. · 31.20 Impact Factor
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ABSTRACT: In clinical settings with fixed resources allocated to predictive genetic testing for high-risk cancer predisposition genes, optimal strategies for mutation screening programmes are critically important. These depend on the mutation spectrum found in the population under consideration and the frequency of mutations detected as a function of the personal and family history of cancer, which are both affected by the presence of founder mutations and demographic characteristics of the underlying population. The results of multistep genetic testing for mutations in BRCA1 or BRCA2 in a large series of families with breast cancer in the French-Canadian population of Quebec, Canada are reported. A total of 256 high-risk families were ascertained from regional familial cancer clinics throughout the province of Quebec. Initially, families were tested for a panel of specific mutations known to occur in this population. Families in which no mutation was identified were then comprehensively tested. Three algorithms to predict the presence of mutations were evaluated, including the prevalence tables provided by Myriad Genetics Laboratories, the Manchester Scoring System and a logistic regression approach based on the data from this study. 8 of the 15 distinct mutations found in 62 BRCA1/BRCA2-positive families had never been previously reported in this population, whereas 82% carried 1 of the 4 mutations currently observed in > or =2 families. In the subset of 191 families in which at least 1 affected individual was tested, 29% carried a mutation. Of these 27 BRCA1-positive and 29 BRCA2-positive families, 48 (86%) were found to harbour a mutation detected by the initial test. Among the remaining 143 inconclusive families, all 8 families found to have a mutation after complete sequencing had Manchester Scores > or =18. The logistic regression and Manchester Scores provided equal predictive power, and both were significantly better than the Myriad Genetics Laboratories prevalence tables (p<0.001). A threshold of Manchester Score > or =18 provided an overall sensitivity of 86% and a specificity of 82%, with a positive predictive value of 66% in this population. In this population, a testing strategy with an initial test using a panel of reported recurrent mutations, followed by full sequencing in families with Manchester Scores > or =18, represents an efficient test in terms of overall cost and sensitivity.Journal of Medical Genetics 02/2007; 44(2):107-21. · 5.70 Impact Factor
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ABSTRACT: 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.The American Journal of Human Genetics 12/2007; 81(5):873-83. · 11.20 Impact Factor