SMARCA4 pathogenic variants: Gynecological cancer histories from a laboratory tested cohort

To describe the cancer histories of individuals with a SMARCA4 germline pathogenic/likely pathogenic variant (gPV) obtained through clinical laboratory-based testing to aid in informing guidance surrounding surveillance and prevention for individuals with gPV.

This retrospective cohort study analyzed individuals with a SMARCA4 gPV identified by multigene panel testing for hereditary cancer at a single commercial clinical laboratory (2014-2024). Descriptive statistics were used to summarize individuals with a gPV in SMARCA4. Age at diagnosis of small cell carcinoma of the ovary hypercalcemic type (SCCOHT) and of unspecified ovarian cancer among individuals with a SMARCA4 gPV was enumerated using cumulative distribution functions.

Among genotyped individuals, 137 had a SMARCA4 gPV. After applying exclusion criteria, 127 individuals were included in the analysis. Individuals with a SMARCA4 gPV were predominately female (74.8 %), and 53.5 % (n = 68) had a history of cancer. Of the females with a cancer history, SCCOHT (17.9 %) and ovarian cancer not otherwise specified (7.4 %) were reported. SCCOHT accounted for 29.8 % of cancer diagnoses among females aged ≤50 years. All SCCOHT cases among individuals with SMARCA4 gPVs were diagnosed by age 40.

Our data support the inclusion of SMARCA4 in genetic testing for hereditary early-onset ovarian cancer, enumerate the ages of SCCOHT diagnosis, and highlight the need for prospective penetrance studies to improve counseling and management for patients and their families.