RT Journal Article
SR Electronic
T1 Sensitivity and specificity of loss of heterozygosity analysis for the classification of rare germline variants in <em>BRCA1/2</em>: results of the observational AGO-TR1 study (NCT02222883)
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 248
OP 252
DO 10.1136/jmedgenet-2020-107353
VO 59
IS 3
A1 Hauke, Jan
A1 Harter, Philipp
A1 Ernst, Corinna
A1 Burges, Alexander
A1 Schmidt, Sandra
A1 Reuss, Alexander
A1 Borde, Julika
A1 De Gregorio, Nikolaus
A1 Dietrich, Dimo
A1 El-Balat, Ahmed
A1 Kayali, Mohamad
A1 Gevensleben, Heidrun
A1 Hilpert, Felix
A1 Altmüller, Janine
A1 Heimbach, André
A1 Meier, Werner
A1 Schoemig-Markiefka, Birgid
A1 Thiele, Holger
A1 Kimmig, Rainer
A1 Nürnberg, Peter
A1 Kast, Karin
A1 Richters, Lisa
A1 Sehouli, Jalid
A1 Schmutzler, Rita K
A1 Hahnen, Eric
YR 2022
UL http://jmg.bmj.com/content/59/3/248.abstract
AB 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.