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Implications of incidental germline findings identified in the context of clinical whole exome sequencing (WES) for guiding cancer therapy.

1581 Background: The identification of incidental germline mutations in the context of next-generation sequencing to guide therapy for cancer patients has become an unintended consequence of advancing technologies. While not the primary goal, additional information buried within the genomic data generated could be important for family members to better understand inherited disease risks and take action. While targeted gene panels are predominantly used in practice, comprehensive WES is becoming increasingly more common. The broader use of WES increases the complexity and scope of potential cancer and non-cancer pathogenic germline variation. Methods: 582 adult metastatic cancer patients from the Indiana University Health Precision Genomics Program were sequenced with tumor and germline CLIA-based WES. The primary intent was for guiding cancer therapy. Germline variant call files were mined for pathogenic/likely pathogenic (P/LP) variants using the ClinVar database. Clinvar classifications were narrowed only to high quality submitters. Results: We identified 1,454 P/LP variants in 209 genes. 92% of patients harbored at least one variant. 72 P/LP variants were identified in 19 cancer predisposition genes with BRCA2 being the most common. 63 patients (10.8%) carried a P/LP variant in a gene that would be recommended by the ACMG to be reported due to clinical actionability with the most common being ATP7B (N = 17), BRCA2 (n = 13), MUTYH (n = 8), and BRCA1 (n = 5). We observed a preponderance of patients who carried autosomal recessive non-cancer pathogenic mutations of varying penetrance. Notable mutated genes included CFTR (cystic fibrosis, n = 16), BTD (biotinidase deficiency, n = 43), and CBS (homocystinuria, n = 90). Of 209 mutated genes, 173 genes had mutations present in less than 1% of our population, demonstrating significant genetic heterogeneity. Conclusions: The majority of patients undergoing clinical cancer WES harbor pathogenic germline variation. Identification of clinically actionable germline findings will create additional burden on oncology clinics as broader WES becomes commonplace.