Dataset Information

Selected abstracts submitted to the Fourth International Symposium on Hereditary Breast and Ovarian Cancer

ABSTRACT: 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.

SUBMITTER: van Asperen C

PROVIDER: S-EPMC3320236 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:The comprehensive assessment of inherited mutations in cancer susceptibility genes helps to optimize clinical decision-making. Conventional laboratory methods based on ngs focus on the detection of single nucleotide variants, small insertions/deletions, and certain copy-number changes in accessible regions of a patient’s dna. Other clinically significant alterations are invisible to these approaches, and for this reason their clinical impact is less well studied. We investigated the prevalence of technically challenging mutations in a large (n = 80,000) patient population focusing on 19 genes (including BRCA1 and BRCA2) associated with breast and/or ovarian cancer. Technical methods beyond conventional next-generation sequencing (ngs) were used to detect and confirm the presence of dna alterations in these patients. We found that 8.6% of patients with a potentially actionable result harbored a mutation not easily detected by conventional ngs sequencing or copy number methods. No single class of mutation was responsible for this—rather, a diversity of challenges was present. Most of these mutations were individually extremely rare, although some were recurrent. Many would have clinical relevance in either a germline or somatic context. Laboratory studies generally include few, if any, of these technically challenging variants. To help evaluate and improve methodologies across laboratories, we constructed a synthetic specimen containing 22 challenging variants in 7 cancer genes. This specimen was provided to collaborating laboratories who sequenced it using a total of 10 different ngs tests. Only 10 of the 22 challenging variants were detected by all tests, and just 3 tests detected all 22. Some but not all of these limitations were previously known. In summary, technically challenging pathogenic variants are collectively prevalent in patients, although methods to detect these variants are not yet uniformly implemented. The clinical data and specimen described here are now available and mght help improve the assessment of cancer risk internationally.

Dataset Information

Selected abstracts submitted to the Fourth International Symposium on Hereditary Breast and Ovarian Cancer

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets