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Original research
Retesting of women who are negative for a BRCA1 and BRCA2 mutation using a 20-gene panel
  1. Jordan Lerner-Ellis1,2,3,
  2. Victoria Sopik4,
  3. Andrew Wong1,
  4. Conxi Lázaro1,4,5,
  5. Steven A Narod4,
  6. George S Charames1,2,3
  1. 1 Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada
  2. 2 Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  3. 3 Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
  4. 4 Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada
  5. 5 Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Hospital Duran i Reynals, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet, Barcelona, Spain
  1. Correspondence to Dr Jordan Lerner-Ellis, Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada; jordan.lerner-ellis{at}


Background The value of retesting women who previously tested negative for a pathogenic variant (mutation) in BRCA1 and BRCA2 using an expanded panel of breast and ovarian cancer genes is unclear.

Methods We studied 110 BRCA1/2-negative women who were retested using a panel of 20 breast and/or ovarian cancer susceptibility genes at the Advanced Molecular Diagnostics Laboratory (AMDL) at Mount Sinai Hospital in Toronto between March 2017 and March 2019. All patients had previously tested negative for BRCA pathogenic variants at the AMDL between January 2012 and March 2018 and were subsequently referred for retesting by their physician.

Results Overall, six pathogenic variants in genes other than BRCA1 and BRCA2 were found (prevalence 5.5%). There were two pathogenic variants found in RAD51C, and one found in each of BRIP1, PALB2, PMS2 and PTEN. The prevalence of pathogenic variants was 6.5% for women affected with cancer (6 of 93), including 4.9% for women with breast cancer (4 of 82) and 22.2% for women with ovarian cancer (2 of 9). None of the 17 unaffected women had a clinically significant or pathogenic variant. There were 44 women (40%) for whom the result of the panel test was inconclusive due to the detection of a variant of uncertain significance.

Conclusions Our findings indicate that the retesting of BRCA1/2-negative individuals with an expanded panel of 20 breast and ovarian cancer genes can produce clinically relevant results, with a yield of 5.5% for pathogenic variants in genes other than BRCA1 and BRCA2.

  • gene panel
  • BRCA1/2 negative
  • hereditary breast and ovarian cancer
  • retesting

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  • Contributors SAN and JL-E planned the study. JL-E, AW, GSC, CL conducted the study and collected the data. VS analysed the data and wrote the manuscript. All authors reviewed the manuscript for intellectual content.

  • Funding This study was supported by the Ontario Ministry of Health. CL was a visiting scientist at Pathology and Laboratory Medicine, Mount Sinai Hospital and Women’s College Hospital thanks to Salvador Madariaga (PRX18/00267) and M-BAE (BA18/00018) grants (Spanish Government).

  • Disclaimer The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The research ethics board at Mount Sinai Hospital approved this study (REB# 13-0124-C).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.