Prevalence of Pathogenic Germline Variants in Cancer Susceptibility Genes using the All of Us Dataset

ImportanceUnderstanding the prevalence of the pathogenic germline variants in cancer susceptibility genes within a non-selected population could be highly beneficial for evaluating the need for broader genetic testing guidelines and thereby aiding early detection of cancer. ObjectiveTo determine the population-level prevalence of pathogenic variants in specific cancer susceptibility genes, which are typically screened for only in individuals with cancer or their at-risk relatives due to cost considerations. We will further breakdown the variant prevalence by race, ethnicity and sex DesignCancer susceptibility genes were selected based on the Invitae Multi-Cancer panel. SettingThis population-based genomic study utilized short-read whole genome sequencing (srWGS) data from the All of Us (AoU) controlled tier database v8. ParticipantsA total of 414,830 individuals with srWGS data and variant information were included in the analysis. Main Outcomes and MeasuresWe extracted the ClinVar variant consequences for each participant and applied stringent criteria to classify variants as truly pathogenic or likely pathogenic (P/LP). A total of 3,454 unique P/LP variants were identified across 77 transcripts and 72 genes. ResultsWe identified 20,968 individuals with P/LP variants, representing approximately 5.05% of the total population. Pathogenic variant prevalence did not significantly differ by sex and ethnicity, while significant differences were observed across racial groups (adj p < 0.0001), with white participants having the highest prevalence (5.72%) and Asians the lowest. Among individual genes, MUTYH (1.33%) had the highest prevalence, followed by BRCA2 (0.42%) and MITF (0.37%). Pathogenic variants in TP53 showed significant sex-based differences, while a higher number of genes had significantly different carrier rates across ethnicity (7) and racial groups (14). Conclusions and RelevanceThe pathogenic variant prevalence found in the general population, along with its racial variability, highlights the need to reconsider current genetic testing guidelines. Expanding screening recommendations could enhance early cancer detection and prevention efforts ultimately reducing disease burden and improving outcomes. Key PointsO_ST_ABSQuestionsC_ST_ABSWhat are the population-level prevalence rates of pathogenic germline variants in specific cancer susceptibility genes? FindingsAmong 414,830 participants with short read whole genome sequencing data from the All of Us dataset, 5.05% carried a pathogenic or likely pathogenic variant in one of 84 cancer susceptibility genes identified from the Invitae Multi-Cancer Panel. MeaningThese findings suggest that pathogenic variants are sufficiently common to support broader genetic screening programs for cancer predisposition, enabling early detection and targeted prevention strategies.