Genetic spectrum of cancer susceptibility: Insights from a 6,093-patient real-world cohort in Singapore.

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Background: Compared to populations of European-descent, prevalence of pathogenic germline variants in cancer predisposition genes is poorly-defined in Asian populations. Here, we investigate genetic spectrum in cancer susceptibility in the Singapore real-world cancer cohort. Methods: The cancer cohort comprised patients referred to Cancer Genetics Service at the National Cancer Center Singapore (Feb 2014-Nov 2025), who underwent multi-gene panel testing. Predictive testing cases were excluded and only the probands were analyzed. Demographics, medical/family history, and genetic results were prospectively collected via REDCap (v13.1.30). Results: The cohort (N=6093) included Chinese (n=4601, 75.5%), Malay (n=516, 8.5%), and Indian (n=358, 5.9%) patients. Predominant diagnoses were breast (3477/6093, 57.1%) and ovarian (998/6093, 16.4%) cancers. Multiple cancers occurred in 11.6% (707/6093), of which 17.5% (124/707) had combined breast and ovarian cancers. Overall, 19.6% (1195/6093) were positive variant (PV) carriers, primarily in BRCA2 (17.7%), BRCA1 (16.2%), and PALB2 (4.4%). PV rates varied significantly: Chinese patients (18.1%) had lower rates compared to Malay (24.0%, p=0.0035) and Indian patients (24.6%, p=0.0078), with no significant difference between the latter two (p>0.05). Among 669 patients with variant reclassification, 61 (9.1%) novel PV carriers were identified, primarily upgraded from VUS. With a median time to reclassification of 1.55 years, upgraded PVs were most frequently observed in BRCA1 (18.0%), ATM (11.5%), MLH1 (9.8%), and POLE (9.8%). Crucially, 16 pedigrees pursued cascade testing, identifying 33 asymptomatic PV carriers who subsequently became eligible for high-risk surveillance. Conclusions: Leveraging Asia's largest multi-ethnic hereditary cancer cohort with up to 11 years of follow-up, this study highlights the clinical value of Singapore's diverse demographic. It also establishes the critical necessity of continuous VUS reassessment. Systematic, long-term VUS tracking is indispensable for optimizing timely interventions and improving cancer prevention.

Reclassified variants and cascade testing outcomes.