Clinical utility of reporting research genetic predisposition testing results to Total Cancer Care participants.

10602 Background: The American College of Medical Genomics and Genetics (ACMG) has identified genes with highly penetrant phenotypes with treatment, prevention, or early disease identification strategies called secondary findings (SF) genes. ACMG recommends clinical laboratories report pathogenic/likely pathogenic (P/LP) SF variants identified during genomic testing. Cancer patients may undergo germline sequencing as part of research studies that can identify valuable SF variants. The objective of this institutional sub-study is to evaluate the feasibility of using ACMG SF genes to assess hereditary disease risk in a cancer population undergoing research sequencing. Methods: Between June 2017 and January 2021, patients unselected for family history, disease site, or stage enrolled in the prospective, observational Total Cancer Care study. Patients underwent research-grade germline whole exome sequencing, with bioinformatic analysis in a CLIA certified laboratory to identify P/LP variants in any ACMG SF v2.0 genes. P/LP variants were reported to treating oncologists with recommendations for genetic counseling referral. We assessed if patients with P/LP variants met NCCN guideline-directed germline testing criteria to quantify benefit from reporting research results. Results: We enrolled 786 patients, which included those with gynecologic (182, 23%), colorectal (124, 16%), lung/bronchus (83, 11%), and head/neck (82, 10%) cancers. The median age was 61 (IQR 52-68) years, 57% were female, 96% were non-Hispanic White, 51% had stage III/IV disease, and 64% resided in an Appalachian community. We identified 57 patients (7%) with cancer predisposition and 14 (2%) with other hereditary disease variants. 2021 NCCN guideline-directed testing would have missed 59% (42/71) of these patients. Incremental high penetrance cancer gene variants included: BRCA1 – endometrial cancer (n = 1); BRCA2– cholangiocarcinoma (n = 1), colon neuroendocrine tumor (n = 1), and lung (n = 2), endometrial (n = 1), and non-epithelial ovarian (n = 1) cancers; MSH6 – duodenal cancer (n = 1); SDHAF2 – non-melanoma skin cancer (n = 1); SDHB – head/neck cancer (n = 1); and TP53 – CNS tumor (n = 1) and head/neck cancer (n = 1). We identified patients at risk for other hereditary diseases including hypertrophic/dilated cardiomyopathy (n = 1), malignant hyperthermia (n = 3), arrhythmogenic right ventricular cardiomyopathy (n = 1), Romano-Ward long QT / Brugada syndromes (n = 4), familial hypercholesterolemia (n = 4), and ornithine transcarbamylase deficiency (n = 1). Conclusions: Reporting germline variants identified during research sequencing is feasible and can benefit cancer patients and their relatives. Though not traditionally assessed, non-cancer predisposition genetic variants may have important intervention opportunities and unexpected patterns may have oncologic implications that require further study.