Prevalence of Variants of Uncertain Significance in Patients Undergoing Genetic Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome

Simple Summary The increasing advancements in genetic testing have led to a rise in the number of patients undergoing cancer genetic testing who receive a VUS (variant of uncertain significance) result. This outcome leaves both patients and their healthcare providers perplexed, as they are unsure about the actual cancer risk and the necessary preventive measures. To address this issue, our retrospective study aimed to assess the occurrence of VUSs in patients tested for two prevalent cancer genetic syndromes. Additionally, we sought to explore the demographic and clinical characteristics of the population who received a VUS result. Our findings revealed that nearly one third of patients tested for common cancer genetic syndromes obtained a VUS test result. Furthermore, we discovered that age, personal history of breast cancer, and family history of breast or ovarian cancer were associated with VUS results. Further research is imperative to identify individuals at risk of receiving a VUS report and, more importantly, to develop tests that can accurately determine the associated cancer risk.Abstract Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS) are the most common inherited cancer syndromes identified with genetic testing. Testing, though, commonly reveals variants of uncertain significance (VUSs). This is a retrospective observational study designed to determine the prevalence of pathogenic mutations and VUSs in patients tested for HBOC and/or LS and to explore the characteristics of the VUS population. Patients 18-80 years old that met NCCN criteria for HBOC and/or LS genetic screening were tested between 2006 and 2020 at Mount Auburn Hospital in Cambridge, Massachusetts. A total of 663 patients were included in the study, with a mean age of 50 years old and 90% being females. Pathogenic mutations were identified in 12.5% and VUSs in 28.3%. VUS prevalence was associated with race (p-value = 0.019), being particularly higher in Asian populations. Patients with a personal history of breast cancer or family history of breast or ovarian cancer were more likely to have a VUS (personal breast: OR: 1.55; CI: 1.08-2.25; family breast: OR: 1.68; CI: 1.08-2.60, family ovarian OR: 2.29; CI: 1.04-5.45). In conclusion, VUSs appear to be detected in almost one third patients tested for cancer genetic syndromes, and thus future work is warranted to determine their significance in cancer development.