UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes; RAD51C, RAD51D, BRIP1 and PALB2

Germline pathogenic variants (GPV) in the cancer predisposition genes BRCA1, BRCA2, MLH1, MSH2, MSH6, BRIP1, PALB2, RAD51D and RAD51C are identified in approximately 15% of patients with ovarian cancer. Whilst there are clear guidelines around clinical management of cancer risk in patients with GPV in BRCA1, BRCA2, MLH1, MSH2 and MSH6, there are few guidelines on how to manage the more moderate ovarian cancer risk in patients with GPV in BRIP1, PALB2, RAD51D and RAD51C, with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, whilst recognition of RAD51C and RAD51D as ovarian cancer predisposition genes has been established for several years, an association with breast cancer has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients with non-mucinous ovarian cancer, new data on breast cancer risk and improved estimates of ovarian cancer risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a two-day meeting to reach a national consensus on clinical management of BRIP1, PALB2, RAD51D and RAD51C carriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree consensus, as well as the key recommendations from the meeting.