Somatic-to-germline concordance rates in clinically actionable cancer predisposition genes.

Abstract

540 Background: Somatic tumor testing increasingly identifies pathogenic variants (PVs) that inform cancer treatment decisions. Per 2019 ESMO guidelines, many somatic PVs in cancer susceptibility genes warrant confirmatory germline genetic testing (gGT). Approximately 4-40% of patients have somatic PVs meeting criteria for confirmatory gGT. Detection of germline PVs carries significant clinical implications, including personalized screening, risk-reducing interventions, and cascade testing of at-risk relatives. PVs in cancer predisposition genes are found in approximately 5-10% of breast, 13-25% of ovarian, 6% of metastatic prostate, and 4-7% of pancreatic cancers. However, the concordance between somatic and germline PVs is incompletely characterized. We sought to quantify concordance rates among patients with actionable somatic findings who also underwent gGT. Methods: We conducted a retrospective cohort study of patients diagnosed with BRCA -associated cancers who underwent somatic tumor testing between 2020-2023 at Columbia University Irving Medical Center in New York, NY. Descriptive statistics were used to determine rates of detection of somatic PVs in cancer predisposition genes and their concordance with gGT results. Results: Among 1,033 patients, the mean age was 66.5 years (SD, 12.3); 61.5% were female. The cohort was 50% White, 18% Hispanic, 13% Black, 11% Asian/Other, and 7% unknown. A somatic PV in a cancer predisposition gene was detected in 145 patients (14.0%), with BRCA2 (3.3%) and BRCA1 (1.9%) most frequently identified. Of these, 120 (83%) underwent confirmatory gGT, revealing a germline PV in 29 patients (overall concordance rate of 24.2%). The highest concordance rates were found with BRCA1 (45%), BRCA2 (30%), and PALB2 (30%). One germline PV was detected in MSH2 (14.3%), but not in other Lynch syndrome genes. Conclusions: Among patients with BRCA -associated cancers who underwent both somatic tumor testing and gGT, approximately one quarter demonstrated somatic-germline concordance, with the highest rates observed in BRCA1/2 and PALB2 . These results should be expanded to a broader patient population with non- BRCA associated cancers. As utilization of somatic tumor testing continues to expand, integration of clinical decision support tools may facilitate the identification and management of patients with secondary hereditary findings. Gene PV detected on somatic tumor testing, N (%) Total = 1,033 Receipt of gGT, N (%) Concordance between germline and somatic PVs, N (%) BRCA2 34 (3.3) 30 (88.2) 9 (30.0) BRCA1 20 (1.9) 20 (100.0) 9 (45.0) POLE 15 (1.5) 8 (53.3) 1 (12.5) PALB2 10 (1.0) 10 (100.0) 3 (30.0) BRIP1 9 (0.9) 6 (66.7) 1 (16.7) PMS2 8 (0.8) 6 (75.0) 0 MSH2 7 (0.7) 7 (100.0) 1 (14.3) Other actionable genes ( SDHA, MSH6, RET, MUTYH, MLH1, BAP1, FH, RAD51D, RAD51C, SDHD ) 42 (4.0) 33 (78.6) 5 (15.2) Total 145 (14.0) 120 (82.8) 29 (24.2)