Predicting the likelihood of a BRCA1/2 pathogenic variant being somatic by testing only tumour DNA in non-mucinous high-grade epithelial ovarian cancer

Robert D Morgan, George J Burghel, Nicola Flaum, Michael Bulman, Philip Smith, Andrew R Clamp, Jurjees Hasan, Claire Mitchell, Zena Salih, Emma R Woodward, Fiona Lalloo, Joseph Shaw, Sudha Desai, Emma J Crosbie, Richard J Edmondson, Helene Schlecht, Andrew J Wallace, Gordon C Jayson, D. Gareth R. Evans

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Aims: Clinical guidelines recommend testing both germline and tumour DNA for BRCA1/2 pathogenic variants (PVs) in non-mucinous high-grade epithelial ovarian cancer (NMEOC). In this study, we show that some tumour BRCA1/2 PVs are highly likely to be somatic based on certain clinical and variant characteristics, meaning it may not be necessary to test all NMEOC cases for germline BRCA1/2 PVs. Methods: An observational study that included all tumour BRCA1/2 PVs detected in cases of NMEOC in the Northwest of England between July 2017 and February 2022. All tumour BRCA1/2 PVs were compared with PVs recorded in a prospectively gathered pan-cancer germline BRCA1/2 (gBRCA) testing database for the same geographical region (gBRCA1 PVs=910 and gBRCA2 PVs=922). Tumour BRCA1/2 PVs were categorised as common (≥1%), uncommon (<1%) or absent from the germline database. Results: One hundred and thirteen tumour BRCA1/2 PVs were detected in 111 NMEOC cases. There were 69 germline and 44 somatic variants. The mean age at diagnosis for gBRCA and somatic BRCA1/2 (sBRCA) PVs was 56.9 and 68.5 years, respectively (Student's t-test p<0.0001). All sBRCA PVs were detected in non-familial cases. All tumour BRCA1/2 PVs with a variant allele frequency (VAF) <35% in non-familial cases were somatic variants. Eighty-one per cent of germline-tumour BRCA1/2 PVs were present (common=31, uncommon=25) in the gBRCA testing database, while 89% of somatic-tumour BRCA1/2 PVs were absent (n=39). Conclusions: We predict the likelihood of a tumour BRCA1/2 PV being somatic is 99.8% in non-familial cases of NMEOC diagnosed aged ≥75, where the VAF is ≤30% and there is no regional germline commonality.

Original languageEnglish
Article numberjcp-2022-208369
Pages (from-to)684-689
Number of pages6
JournalJournal Of Clinical Pathology
Issue number10
Early online date23 Jun 2022
Publication statusPublished - 1 Oct 2023


  • Biomarkers, Tumor
  • Ovarian Neoplasms

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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