Somatic profiling guides germline genetic testing in patients with mutations in cancer predisposition genes.

10608 Background: 15% of patients with advanced cancer have an inherited predisposition to cancer. Over a third of patients carrying a pathogenic germline variant would not qualify for genetic testing based on current National Comprehensive Cancer Network genetic testing guidelines. Supplementing the current practice of somatic sequencing with germline testing would improve treatment decisions and be informative of the risk of developing subsequent cancers in the individual. It may also extend the benefits of high-risk screening programs to family members. Offering genetic testing to patients with the highest likelihood of carrying a germline mutation is preferable to unselected sequencing given the current environment. Methods: We developed a list of genes to help identify patients whose somatic mutations were more likely to be found in the germline as well. We classified these genes into 3 tiers based on the likelihood of germline pathogenicity. All somatic sequencing panel results were reviewed based on the IRB-approved protocol for our designated Tier One genes ( ATM, BAP1, BMPR1A, BRCA1, BRCA2, BRIP1, MSH2, MSH6, MUTYH, MYH11, PALB2, RUNX1, SDHAF2, SDHB, SDHC, and known founder mutations in additional genes). Treating physicians for patients whose tumors harbored a mutation in one of these genes were contacted and, if they agreed, patients were offered participation in this ongoing study. Enrolled patients had genetic counseling and testing for a multi-gene panel at no cost to them. Results: We reviewed 3621 somatic test results, and 339 (9.4%) patients were eligible for the study. 34 (10.03%) eligible patients were enrolled, and 33 (9.73%) completed testing. Of these, 16 had positive germline results (48.5%, though they may not all be in the originally identified genes), 8 had a variant of uncertain significance (24.2%), and 9 had negative testing (27.3%). Some patients were not referred by their treating physicians based on their own clinical assessment. Others were hesitant to enroll due to concerns about the privacy of genetic information. Other confounding factors may have affected our accrual, including the pandemic. Conclusions: Implementing a somatic profiling-based screening program to identify inherited cancer predisposition syndromes is feasible in patients who may not meet current germline genetic testing guidelines. Our study showed 9.73% of eligible patients underwent genetic counseling and testing, and an inherited predisposition to cancer was confirmed in almost 50% of these patients. In addition, family members were offered cascade testing. Germline genetic evaluation remains underutilized even when payor constraints are removed as a barrier. To increase the identification of patients with inherited predispositions to cancer other barriers such as a lack of referrals by treating oncologists need to be overcome.