Background We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features. Methods Germline assessment of ≥ 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal MSK-IMPACT sequencing from 1/1/15-6/30/21. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using non-parametric tests. Results Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high-penetrance, 39 [17%] moderate-penetrance, and 117 [51%] low/recessive/uncertain-penetrance). Compared to those without gPVs, patients with gPVs were younger (P=.002), more often White (P=.009), less obese (P=.025) and had differences in distribution of tumor histology (P=.017) and molecular subtype (P<.001). Among 231 gPVs, 74 (32%) exhibited biallelic inactivation within tumors. For high-penetrance gPVs, 63% (47/75) of ECs had biallelic alterations, primarily affecting mismatch repair (MMR) and homologous recombination (HR) genes, including BRCA1/2, RAD51D, and PALB2. Biallelic inactivation varied across molecular subtypes with highest rates in microsatellite instability-high (MSI-H) or copy-number (CN)-high subtypes [3/12 (25%) POLE, 30/77 (39%) MSI-H, 27/60 (45%) CN-H, 9/57 (16%) CN-L, P<.001]. Conclusions Thirteen percent of unselected patients with EC had gPVs, with 63% of gPVs in high-penetrance genes (MMR and HR) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention.

Cancer predictive or diagnostic assays, offered as Laboratory-Developed Tests (LDTs), have been subject to regulatory authority and enforcement discretion by the US Food and Drug Administration. Many LDTs enter the market without US Food and Drug Administration or any regulatory review. The Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Amendments focuses on analytic performance, but has limited oversight of the quality or utility of LDTs, including whether patients have been harmed as a result of their use. Increasingly, LDTs for cancer risk or early detection have been marketed directly to consumers, with many LDT developers depicting these tests, requested by patients but ordered by personal or company-associated physicians, as procedures falling under the practice of medicine. This patchwork of regulation and enforcement uncertainty regarding LDTs and public concerns about accuracy of tests given emergency authorization during the COVID-19 pandemic led to the Verifying Accurate Leading-edge IVCT (in vitro clinical test) Development Act of 2021. This pending federal legislation represents an opportunity to harmonize regulatory policies and address growing concerns over quality, utility, and safety of LDTs for cancer genomics, including tests marketed directly to consumers. We review here questions regarding the potential benefits and harms of some cancer-related LDTs for cancer risk and presymptomatic molecular diagnosis, increasingly marketed to oncologists or directly to the worried well. We offer specific proposals to strengthen oversight of the accuracy and clinical utility of cancer genetic testing to ensure public safety.

The availability and cost of next‐generation sequencing (NSG) now allow testing large numbers of genes simultaneously. However, the gold standard for predictive testing has been to test only for a known family mutation or confirmed family disease. The goal of this study was to investigate the psychological impact of predictive testing for autosomal dominant neurodegenerative diseases without a known family mutation using next‐generation sequencing panels compared to single‐gene testing of a known family mutation. Fourteen individuals from families with a known mutation and 10 individuals with unknown family mutations participated. Participants completed questionnaires on demographics, genetic knowledge, and psychological measures of anxiety, depression, perceived personal control, rumination, and intolerance to uncertainty at baseline and 1 and 6 months after receiving results. Decision regret was measured 1 and 6 months after receiving results. Participants completed a modified Huntington disease genetic testing protocol with genetic counseling and neurological and psychological evaluation. Genetic testing of either the known family mutation or an NGS panel of neurodegenerative disease genes was performed. Semi‐structured interviews were performed at 6 months post‐results about their experience. Two‐sample t tests were performed on data collected at each time point to identify significant between‐group differences in demographic variables, baseline psychological scores, and baseline genetic knowledge scores. Within‐group change over time was assessed by a mixed‐effects model. Results of this study indicate that NGS panels for predictive testing for neurodegenerative disease are safe and beneficial to participants when performed within a modified HD protocol. Though significant differences in psychological outcomes were found, these differences may have been driven by genetic results and baseline psychological differences between individuals within the groups. Participants did not regret their decision to test and were largely pleased with the testing protocol.