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We determined the frequency and mutational spectrum of BRCA1 and BRCA2 in a series of high-risk breast cancer patients from Brazil. A total of 1,267 patients were referred for BRCA genetic testing, and no obligation of fulfilling criteria of mutation probability methods for molecular screening was applied. Germline deleterious mutations in BRCA1/2 (i.e. pathogenic/ likely pathogenic variants) were identified in 156 out of 1267 patients (12%). We confirm recurrent mutations in BRCA1/2, but we also report three novel mutations in BRCA2, not previously reported in any public databases or other studies. Variants of unknown significance (VUS) represent only 2% in this dataset and most of them were detected in BRCA2. The overall mutation prevalence in BRCA1/2 was higher in patients diagnosed with cancer at age > 35 years old, and with family history of cancer. The present data expand our knowledge of BRCA1/2 germline mutational spectrum, and it is a valuable clinical resource for genetic counseling and cancer management programs in the country.

The comprehensive assessment of inherited mutations in cancer susceptibility genes helps to optimize clinical decision-making [...]

A substantial proportion of women who undergo BRCA1/2 testing learn that they carry a variant of uncertain significance[...]

Supplementary Tables. (DOCX 122 kb)

Background: Nearly 15% of DNA tests for BRCA1/2 results in the identification of an unclassified variant (UV). In DNA diagnostic laboratories in The Netherlands, a 4-group classification system (class I to IV) is in use (Bell et al.). Aim of this study was to investigate whether the UVs in different classes showed a significant difference in their in silico characteristics and would justify current differences in protocols for counselling with respect to communication to the counselees. Methods: Missense UVs in BRCA1/2 identified between 2002 and 2010 (n = 88) were analyzed. In silico analysis of UVs was performed using SIFT– analysis Grantham score and AGVGD for the predicted severity of amino acid substitutions. Each UV was classified to one of the four classes. Results: More than half of the UVs (n = 50) were predicted to be tolerated using SIFT-analysis. Accordingly, all these variants are scored as neutral (C0) by AGVGD. Of the remaining 38 UVs not tolerated using SIFT-analysis, 19 were scored as C0 (neutral), 8 were scored C15–C25 (intermediate) and 11 were scored C35 or higher (likely to be pathogenic). Although class III UVs more frequently show in silico parameter outcomes that are suspicious for a pathogenic effect, the observed differences are not absolute. Seven UVs classified in class II had similar in silico profiles with 7 UVs in class III. Conclusion: This study showed that, in general, in silico analysis is consistently applied and proved to be able to discriminate between the different classes of UVs. However, additional analyses will be required to classify the UVs with more accuracy. In order to reduce psychological distress in families in which a UV is identified, we propose that communication of a UV should not primarily depend on its class, but also on the possibility to perform additional research in the family.