Cancer Risk Associated With Pathogenic Variants Identified Using Multigene Hereditary Cancer Panel Testing.

Purpose: -associated clinical syndromes such as Cowden syndrome (CS) increase cancer risk and have historically been diagnosed based upon phenotypic criteria. Because not all patients clinically diagnosed with CS have pathogenic variants (PVs), and not all patients with PVs have been clinically diagnosed with CS, the cancer risk conferred by PVs calculated from cohorts of patients with clinical diagnoses of CS/CS-like phenotypes may be inaccurate.

Methods: We assessed a consecutive cohort of 727,091 individuals tested clinically for hereditary cancer risk, with a multigene panel between September 2013 and February 2022. Multivariable logistic regression models accounting for personal and family cancer history, age, sex, and ancestry were used to quantify disease risks associated with PVs.

Results: PVs were detected in 0.027% (193/727,091) of the study population, and were associated with a high risk of female breast cancer (odds ratio [OR], 7.88; 95% CI, 5.57 to 11.16; = 2.3 × 10), endometrial cancer (OR, 13.51; 95% CI, 8.77 to 20.83; = 4.2 × 10), thyroid cancer (OR, 4.88; 95% CI, 2.64 to 9.01; = 4.0 × 10), and colon polyposis (OR, 31.60; CI, 15.60 to 64.02; = 9.0 × 10). We observed modest evidence suggesting that PVs may be associated with ovarian cancer risk (OR, 3.77; 95% CI, 1.71 to 8.32; = 9.9 × 10). Among patients with similar personal/family history and ancestry, every 5-year increase in age of diagnosis decreased the likelihood of detecting a PV by roughly 60%.

Conclusion: We demonstrate that PVs are associated with significantly increased risk for a range of cancers. Together with the observation that PV carriers had earlier disease onset relative to otherwise comparable noncarriers, our results may guide screening protocols, inform risk-management strategies, and warrant enhanced surveillance approaches that improve clinical outcomes for PV carriers, regardless of their clinical presentation.