Clinical utility of testing for PALB2 and CHEK2 c.1100delC in breast and ovarian cancer

Emma Woodward, Elke Van Veen, Claire Forde, Elaine Harkness, Helen Byers, Jamie Ellingford, Naomi Bowers, Andrew J Wallace, Sacha Howell, Tony Howell, Fiona Lalloo, William Newman, Miriam J Smith, D Gareth Evans

Research output: Contribution to journalArticlepeer-review


Purpose: To investigate the contribution of PALB2 pathogenic gene variants (PGVs, PALB2_PGV) and the CHEK2 c.1100delC (CHEK2_1100delC) PGV to familial breast and ovarian cancer, and PALB2_PGV associated breast cancer pathology. Methods: Outcomes of germline PALB2_PGV and CHEK2_1100delC testing were recorded in 3127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial non-mucinous ovarian cancer and 1567 female controls. Breast cancer pathology was recorded in PALB2_PGV cases from extended families. Results: 35 PALB2 and 44 CHEK2_1100delC PGVs were detected in patients [odds ratio (OR) PALB2 breast-ovarian=5.90 (95% CIs:1.92-18.36), CHEK2 breast-ovarian=4.46 (95% CIs:1.86-10.46); PALB2 breast=6.16 (95% CIs:1.98-19.21), CHEK2 breast=4.89 (95% CIs:2.01-11.34). Grade3-ERpositive-HER2negative, grade3 and triple negative (TN) tumours were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service [respectively: 15/43, 254/1843, P=0.0005; 28/37, 562/1381, P=0.0001; 12/43, 204/1639, P<0.0001). PALB2_PGV likelihood increased with increasing Manchester Score (MS) [MS<15=17/1763, MS 20-39=11/520, P=0.04] but not for CHEK2_1100delC [MS<15=29/1762, MS 20-39=4/520]. PALB2 PGVs showed perfect segregation in 20/20 first degree relatives with breast cancer, compared with 7/13 for CHEK2_1100delC (P=0.002). Conclusion: PALB2 PGVs and CHEK2_1100delC together account for ~2.5% of familial breast/ovarian cancer risk. PALB2 PGVs are associated with grade3, TN and grade3-ERpositive-HER2negative breast tumours.
Original languageEnglish
JournalGenetics in Medicine
Publication statusAccepted/In press - 13 May 2021


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