Prevalence of microsatellite stable Lynch syndrome and universal germline testing: A pan-cancer analysis of 246,694 patients.

10613 Background: Lynch Syndrome (LS) is an inherited cancer syndrome that confers up to a 60% lifetime risk of colorectal (CRC), endometrial (EC), or other cancers, and up to a 40% risk of a second primary cancer. The current standard-of-care includes LS screening upon the diagnosis of CRC or EC (especially in patients < 50 years old or with a strong family history) via immunohistochemistry for mismatch repair (MMR) protein deficiencies or microsatellite instability (MSI) testing algorithms; germline genetic testing is subsequently performed in MMR-deficient cases for confirmation . To assess the concordance between MSI status and LS, we evaluated the proportion of patients with pathogenic or likely pathogenic germline variants in a LS gene (LS-PGVs) who had microsatellite stable (MSS) tumors. Methods: We analyzed a pan-cancer cohort (n = 246,694) of patients who underwent personalized ctDNA testing (Signatera, Natera, Inc.), which involved whole exome sequencing (WES) of tumor and matched normal samples. MSI status was assessed in the tumor WES data by the MSISensor2 algorithm (MSI-H was defined as score ≥6.5). Germline single-nucleotide variants and short insertions/deletions from germline WES were identified and annotated with Variant Effect Predictor (v.105). The pathogenicity of variants in LS genes ( EPCAM , MSH2 , MSH6 , MLH1 , and PMS2 ) was determined using classifications available in the ClinVar database. Results: The pan-cancer cohort largely consisted of patients with CRC (n = 107,907; 44% of cohort), breast (n = 55,330; 22%), and other cancer types (each ≤4% of cohort) including EC (n = 5519; 2%). MSI status was determined in 84% (207,536/246,694) of the cohort, of whom 93% (193,110/207,536) had MSS tumors. LS-PGVs were identified in 1% (2418/207536) of the MSI-scored pan-cancer cohort. Among all pan-cancer patients with LS-PGVs, 36% (862/2418) had MSS tumors. Most patients with EPCAM PGVs (91%; 32/35) had MSS tumors. Conversely, only 17% (101/588) of patients with MLH1 PGVs had MSS tumors. We next assessed concordance between LS-PGVs and MSI status in CRC and EC. Among CRC patients with an MSI score (n = 97,309), 12% (11,752/97,309) had MSI-H and 88% (85,554/97,309) had MSS tumors. Further, LS-PGVs were identified in 2% (1,759/97,309), of whom 25% (437/1,759) had MSS tumors. In EC patients with MSI scores (n = 4,625), 20% (926/4625) had MSI-H and 80% (3699/4625) had MSS tumors. Of these, LS-PGVs were identified in 2% (86/4625) among whom 44% (38/86) had MSS tumors. Conclusions: LS-PGV yield was 2% for both CRC and EC, and a substantial proportion of these patients had MSS tumors (CRC: 25%; EC: 44%). Given the high risk for secondary cancers associated with LS and the implications for cascade testing, these findings strengthen the existing recommendation for considering broader germline screening of all EC and CRC patients for LS.