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| Item Type: | Article |
|---|---|
| Title: | Sensitivity and specificity of loss of heterozygosity analysis for the classification of rare germline variants in BRCA1/2: results of the observational AGO-TR1 study (NCT02222883) |
| Creators Name: | Hauke, J., Harter, P., Ernst, C., Burges, A., Schmidt, S., Reuss, A., Borde, J., De Gregorio, N., Dietrich, D., El-Balat, A., Kayali, M., Gevensleben, H., Hilpert, F., Altmüller, J., Heimbach, A., Meier, W., Schoemig-Markiefka, B., Thiele, H., Kimmig, R., Nürnberg, P., Kast, K., Richters, L., Sehouli, J., Schmutzler, R.K. and Hahnen, E. |
| Abstract: | Variant-specific loss of heterozygosity (LOH) analyses may be useful to classify BRCA1/2 germline variants of unknown significance (VUS). The sensitivity and specificity of this approach, however, remains unknown. We performed comparative next-generation sequencing analyses of the BRCA1/2 genes using blood-derived and tumour-derived DNA of 488 patients with ovarian cancer enrolled in the observational AGO-TR1 trial (NCT02222883). Overall, 94 pathogenic, 90 benign and 24 VUS were identified in the germline. A significantly increased variant fraction (VF) of a germline variant in the tumour indicates loss of the wild-type allele; a decreased VF indicates loss of the variant allele. We demonstrate that significantly increased VFs predict pathogenicity with high sensitivity (0.84, 95% CI 0.77 to 0.91), poor specificity (0.63, 95% CI 0.53 to 0.73) and poor positive predictive value (PPV; 0.71, 95% CI 0.62 to 0.79). Significantly decreased VFs predict benignity with low sensitivity (0.26, 95% CI 0.17 to 0.35), high specificity (1.0, 95% CI 0.96 to 1.00) and PPV (1.0, 95% CI 0.85 to 1.00). Variant classification based on significantly increased VFs results in an unacceptable proportion of false-positive results. A significantly decreased VF in the tumour may be exploited as a reliable predictor for benignity, with no false-negative result observed. When applying the latter approach, VUS identified in four patients can now be considered benign. Trial registration number NCT02222883. |
| Keywords: | BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, BRCA1 Genes, Genetic Predisposition to Disease, Germ Cells, Germ-Line Mutation, Loss of Heterozygosity, Ovarian Neoplasms |
| Source: | Journal of Medical Genetics |
| ISSN: | 0022-2593 |
| Publisher: | BMJ Publishing Group |
| Volume: | 59 |
| Number: | 3 |
| Page Range: | 248-252 |
| Date: | March 2022 |
| Official Publication: | https://doi.org/10.1136/jmedgenet-2020-107353 |
| PubMed: | View item in PubMed |
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