Genetic testing for RAD51C mutations: in the clinic and community

Abstract

Much of the observed familial clustering of breast and ovarian cancer cannot be explained by mutations in BRCA1 and BRCA2. Several other cancer susceptibility genes have been identified, but their value in routine clinical genetic testing is still unclear. Germline mutations in RAD51C have been identified in about 1% of hereditary breast and ovarian cancer families. RAD51C mutations are predominantly found in families with a history of ovarian cancer and are rare in families with a history of breast cancer alone. RAD51C is primarily an ovarian cancer susceptibility gene. A mutation is present in approximately 1% of unselected ovarian cancers. Among mutation carriers, the lifetime risk of ovarian cancer is approximately 9%. The average age at onset is approximately 60 years; this suggests that preventive oophorectomy can be delayed until after natural menopause. Under current guidelines, genetic testing for RAD51C is expected to have a limited impact on ovarian cancer incidence at a population level. This is because the penetrance is 9% to age 80; the great majority of families with mutations would be represented by a single case of ovarian cancer, these are potentially preventable through population screening but not through screening of established ovarian cancer families.

Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 HBOC families

“…We also suggest prophylactic salpingo-oophorectomy for menopausal carrier women in ovarian cancer families with RAD51C and RAD51D PVs as ORs conferred by PVs detected within these genes are comparable to those conferred by BRCA2 PVs. 15,[30][31][32] We also confirmed the moderate cancer risks induced by CHEK2 and BRIP1 PVs. However, considering the moderate ORs for breast cancer conferred by CHEK2 PVs (1.77 [1.20-2.48]), and for ovarian cancer induced by BRIP1 PVs 3.82 [1.66-7.11], it appears inappropriate to base clinical management on these variants.…”

Mutation status of RAD51C,PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations

“…They demonstrated that these mutations are detected in 1.3% of probands with family history of both breast and ovarian cancer, but not in probands with family history of only breast cancer. (19) Similarly, most deleterious mutations were identified in families of patients with both breast and ovarian cancer, (20)(21)(22) although a few cases were identified in a family including only patients with breast cancer. (23)(24)(25) In addition, Osorio et al reported that the prevalence of RAD51C mutation in a family of patients with ovarian cancer was 1%, while the value in a family including only patients with breast cancer was 0.2%.…”

Drugging the Cancers Addicted to DNA Repair

“…In addition to defects in BRCA1 or 2, cancer genome sequencing revealed mutations in many other HR pathway components that promote oncogenesis, including PALB2 (112), BRCA1-interacting protein 1 ( BRIP1 ; also termed FANCJ and BACH1 ) (113), BARD1 (114), BAP1 (115) and RAD51C (116). This expansion of HR driver mutations should broaden the clinical application of PARP1 inhibitors (117).…”