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Abstract Background Cancer is a major cause of death, and its early identification and intervention have potential for clinical actionability and benefits for human health. The studies using whole‐genome sequencing (WGS) and large samples analysis of cancer‐related genes have been rarely done. Methods We performed WGS to explore germline mutations in coding and non‐coding areas of cancer‐related genes and non‐coding driver genes and regulatory areas. Structural variants (SVs) was also analyzed. We used several tools and a subgrouping method to analyze the variants in 1491 healthy participants. Moreover, 275 cancer‐related genes sequencing was carried out in 125 cancer patients. Results The incidence of familial cancer in the Taiwanese general population is 8.79% (131/1491). Cancer carrier rate of cancer‐related genes is about 7.04% (105/1491) for pathogenic/likely pathogenic variants (P/LP) on ClinVar database only, and 28.24% (421/1491) for P/LP and loss of function variants. The carrier frequencies of cancer‐related genes P/LP on ClinVar database were as follows: 8.40% (11/131), 7.11% (28/394), and 6.83% (66/966) in FC, 1MC, and nMC, respectively. The SVs and non‐coding driver gene variants are uncommon. There are 1.54% (23/1491) of actionable cancer genes in American College of Medical Genetics and Genomics (ACMG), and the germline mutation rate of 275 cancer‐related genes is 7.2% (9/125) in cancer patients including 4.0% (5/125) of actionable cancer genes in ACMG. After analyzing the frequencies of P/LP variants on GJB2 and SLC25A13 genes, we suggest that these two genes may not be cancer‐related genes and need be re‐evaluated. Conclusions WGS analysis can completely detect germline mutations in cancer carriers. This study use subgrouping approach for samples provides a strategy to study whether a gene or variant is a cancer‐related gene or variant in the future studies.