Sequential tumor molecular profiling identifies likely germline variants

Purpose: To identify likely germline DNA variants from sequential tumor profiling data from hematopoietic malignancies (HMs). Methods: The coefficient of variance was calculated from variant allele frequency of next generation sequencing assays. Variants' likelihood of being germline was ranked on a 1 to 5 scale. Outcomes were examined in patients with such variants. Results: In a pilot set of 33 genes, 89% of grade 1, 77% of grade 2, 62% of grade 3, 52% of grade 4, and 21% of grade 5 variants were confirmed to be germline. Among those, 22% were pathogenic or likely pathogenic in genes recognized as conferring hereditary HM risk, including BRCA1/2, CHEK2, CSF3R, and DDX41. To determine if this approach identified genes with known autosomal dominant inheritance, we analyzed sequential data from 1336 genes in 1135 HM patients. Among unique variants, 16% occurred in hereditary HM genes, and 15% were deleterious. Patients with grade 1/2 alleles had decreased survival 2 years after initial molecular testing (78% versus 88%, P = .0037) and increased all -cause mortality compared with those without (hazard ratio 2.02, 95% CI 1.18-3.46, P = .019). Conclusion: Variant germline status may be predicted using sequential tumor profiling and patients with likely germline variants experience inferior outcomes compared with those without. (c) 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.