Growing evidence shows a role for other genes that may disclose new clinical care options for hereditary uterine cancer (UC), which has historically been linked to pathogenic/likely pathogenic germline variations (PGVs) in genes involved in Lynch syndrome or PTEN. To evaluate the frequency and potential clinical significance of PGVs discovered in UC patients submitted for full germline genetic testing, researchers included testing for Lynch syndrome, PTEN, and other cancer risk genes. This retrospective study evaluated the prevalence of PGVs by syndrome type, patient age at testing, and self-reported ancestry among patients referred to a single clinical lab for germline genetic testing for an indication of uterine or endometrial cancer. Clinical recommendations for management, targeted medicines, and participation in clinical trials were used to assess the potential clinical actionability of PGVs. PGVs were found in 13.6% (or 880/6490). Lynch syndrome genes (60.4%) and PTEN (1.5%) had the highest frequency of PGVs, followed by other cancer risk genes (i.e., CHEK2, BRCA1/BRCA2) at 38.1%. Both patients, less than and more than or equal to 50 years old, had similar rates of PGV prevalence (15.1% and 13.2%, respectively). A large majority of PGVs (97.2%) were linked to recommended management according to guidelines, such as cascade testing; 60.5% were linked to medicines that have received Food and Drug Administration (FDA) approval; and 35.2% were linked to clinical studies. It is possible that a sizable fraction of UC patients who carry actionable PGVs will go unnoticed if germline testing is restricted to patients less than  50 years old at diagnosis and is focused solely on Lynch syndrome genes and PTEN. Many people, including those with UC and their at-risk relatives, could benefit from universal, comprehensive genetic testing of UC patients.

Source: sciencedirect.com/science/article/pii/S0090825822003341