International journal of gynecological cancer : official journal of the International Gynecological Cancer Society · 2026
Somatic BRCA1 and BRCA2 detection in homologous recombination deficiency testing: concordance of four sequencing workflows with the Myriad myChoice companion diagnostic.
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Scaglione Giovanni Luca, Roma Cristin, Califano Daniela, Cecere Sabrina Chiara, Lorusso Domenica, Normanno Nicola, Fagotti Anna, Capoluongo Ettore Domenico, Colombo Nicoletta, De Luca Antonella, Beltrame Luca, Pisano Carmela, Russo Daniela, Alberto Lissoni L Andrea, Arenare Laura, Paracchini Lara, Ferrero Annamaria, De Giorgi Ugo, Musacchio Lucia, Perrone Francesco, Marchini Sergio, Pignata Sandro
Аннотация
OBJECTIVE: To assess concordance of tumor BRCA1/BRCA2 variant detection across four sequencing workflows benchmarked against the Myriad myChoice companion diagnostic in newly diagnosed ovarian cancer.
METHODS: Within the MITO16A/MaNGO-OV2 trial, 100 formalin-fixed paraffin-embedded ovarian cancer samples were analyzed across four workflows in the Italian network: one academic modular workflow (Agilent OneSeq/VarDict) and three commercial platforms (Oncomine Comprehensive Assay Plus/Ion Reporter, SOPHiA DDM, and TruSight Oncology 500/DRAGEN). BRCA1/BRCA2 calls were compared with myChoice as the reference. Variant classification, quality metrics, and copy number findings were centrally curated. Concordance was assessed at the sample level, and discordant cases underwent manual review to identify technical or interpretive drivers.
RESULTS: Two samples failed myChoice testing and were excluded, leaving 98 evaluable cases. Complete agreement across all workflows and the reference assay was observed in 86 of 98 samples (87.8%). The 12 discordant cases (12.2%) fell into four recurrent categories: limited detection of exon-level copy number alterations, low-frequency variants in formalin-fixed paraffin-embedded specimens, differences in reporting of variants of uncertain significance, and transcript or nomenclature inconsistencies. An illustrative sample with dual BRCA1/BRCA2 pathogenic variants highlighted the impact of local coverage and filtering thresholds. No workflow showed systematic over-calling or under-calling.
CONCLUSIONS: Tumor BRCA1/BRCA2 results showed moderate cross-platform concordance, with clinically relevant discordances driven mainly by technical and interpretive factors. Greater standardization of tumor BRCA1/BRCA2 testing is needed to support consistent reporting, treatment decisions, and referral for hereditary cancer assessment.
TRIAL REGISTRATION: EudraCT 2012-003043-29; NCT01706120.
METHODS: Within the MITO16A/MaNGO-OV2 trial, 100 formalin-fixed paraffin-embedded ovarian cancer samples were analyzed across four workflows in the Italian network: one academic modular workflow (Agilent OneSeq/VarDict) and three commercial platforms (Oncomine Comprehensive Assay Plus/Ion Reporter, SOPHiA DDM, and TruSight Oncology 500/DRAGEN). BRCA1/BRCA2 calls were compared with myChoice as the reference. Variant classification, quality metrics, and copy number findings were centrally curated. Concordance was assessed at the sample level, and discordant cases underwent manual review to identify technical or interpretive drivers.
RESULTS: Two samples failed myChoice testing and were excluded, leaving 98 evaluable cases. Complete agreement across all workflows and the reference assay was observed in 86 of 98 samples (87.8%). The 12 discordant cases (12.2%) fell into four recurrent categories: limited detection of exon-level copy number alterations, low-frequency variants in formalin-fixed paraffin-embedded specimens, differences in reporting of variants of uncertain significance, and transcript or nomenclature inconsistencies. An illustrative sample with dual BRCA1/BRCA2 pathogenic variants highlighted the impact of local coverage and filtering thresholds. No workflow showed systematic over-calling or under-calling.
CONCLUSIONS: Tumor BRCA1/BRCA2 results showed moderate cross-platform concordance, with clinically relevant discordances driven mainly by technical and interpretive factors. Greater standardization of tumor BRCA1/BRCA2 testing is needed to support consistent reporting, treatment decisions, and referral for hereditary cancer assessment.
TRIAL REGISTRATION: EudraCT 2012-003043-29; NCT01706120.