• Gene Panel Testing for Breast Cancer Reveals Differential Effect of Prior BRCA1/2 Probability

      Evans, D. Gareth; orcid: 0000-0002-8482-5784; email: Gareth.Evans@mft.nhs.uk; van Veen, Elke M.; orcid: 0000-0001-8618-2332; email: Elke.vanVeen@manchester.ac.uk; Woodward, Emma R.; orcid: 0000-0002-6297-2855; email: Emma.Woodward@mft.nhs.uk; Harkness, Elaine F.; orcid: 0000-0001-6625-7739; email: Elaine.F.Harkness@manchester.ac.uk; Ellingford, Jamie M.; email: jamie.ellingford@manchester.ac.uk; Bowers, Naomi L.; email: Naomi.Bowers@mft.nhs.uk; Wallace, Andrew J.; email: andrew.wallace@mft.nhs.uk; Howell, Sacha J.; email: sacha.howell@manchester.ac.uk; Howell, Anthony; email: Anthony.Howell@manchester.ac.uk; Lalloo, Fiona; email: Fiona.Lalloo@mft.nhs.uk; et al. (MDPI, 2021-08-18)
      Whilst panel testing of an extended group of genes including BRCA1/2 is commonplace, these studies have not been subdivided by histiotype or by a priori BRCA1/2 probability. Patients with a breast cancer diagnosis undergoing extended panel testing were assessed for frequency of actionable variants in breast cancer genes other than BRCA1/2 by histiotype and Manchester score (MS) to reflect a priori BRCA1/2 likelihood. Rates were adjusted by prior testing for BRCA1/2 in an extended series. 95/1398 (6.3%) who underwent panel testing were found to be positive for actionable non-BRCA1/2 breast/ovarian cancer genes (ATM, BARD1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, TP53). As expected, PALB2, CHEK2 and ATM were predominant with 80-(5.3%). The highest rate occurred in Grade-3 ER+/HER2− breast cancers-(9.6%). Rates of non-BRCA actionable genes was fairly constant over all likelihoods of BRCA1/2 but adjusted rates were three times higher with MS 9 (BRCA1/2 = 1.5%, other = 4.7%), but was only 1.6% compared to 79.3% with MS ≥ 40. Although rates of detection of non-BRCA actionable genes are relatively constant across BRCA1/2 likelihoods this disguises an overall adjusted low frequency in high-likelihood families which have been heavily pre-tested for BRCA1/2. Any loss of detection sensitivity for BRCA1/2 actionable variants in breast cancer panels should lead to bespoke BRCA1/2 testing being conducted first.