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

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 3,127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial nonmucinous ovarian cancer, and 1,567 female controls. Breast cancer pathology was recorded in PALB2 _PGV cases from extended families. Results Thirty-five PALB2 and 44 CHEK2 _1100delC PGVs were detected in patients (odds ratio [OR] PALB2 breast–ovarian = 5.90 [95% CI: 1.92–18.36], CHEK2 breast–ovarian = 4.46 [95% CI: 1.86–10.46], PALB2 breast = 6.16 [95% CI: 1.98–19.21], CHEK2 breast = 4.89 [95% CI: 2.01–11.34]). Grade 3 ER-positive HER2-negative, grade 3 and triple negative (TN) tumors were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service (respectively: 15/43, 254/1,843, P = 0.0005; 28/37, 562/1,381, P = 0.0001; 12/43, 204/1,639, P < 0.0001). PALB2 _PGV likelihood increased with increasing Manchester score (MS) (MS < 15 = 17/1,763, MS 20–39 = 11/520, P = 0.04) but not for CHEK2 _1100delC (MS < 15 = 29/1,762, 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 grade 3, TN, and grade 3 ER-positive HER2-negative breast tumors.