Retesting of women who are negative for a <i>BRCA1</i> and <i>BRCA2</i> mutation using a 20-gene panel.

Abstract

The value of retesting women who previously tested negative for a pathogenic variant (mutation) in <i>BRCA1</i> and <i>BRCA2</i> using an expanded panel of breast and ovarian cancer genes is unclear. We studied 110 <i>BRCA1/2</i>-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 <i>BRCA</i> pathogenic variants at the AMDL between January 2012 and March 2018 and were subsequently referred for retesting by their physician. Overall, six pathogenic variants in genes other than <i>BRCA1</i> and <i>BRCA2</i> were found (prevalence 5.5%). There were two pathogenic variants found in <i>RAD51C</i>, and one found in each of <i>BRIP1</i>, <i>PALB2</i>, <i>PMS2</i> and <i>PTEN</i>. 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. Our findings indicate that the retesting of <i>BRCA1</i>/<i>2</i>-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 <i>BRCA1</i> and <i>BRCA2</i>.