A 67-year-old male patient initially presented with belching and abdominal distension for a year as well as diarrhea for over 2 mo. The patient had no history of present symptoms. The patient had a history of hypertension that was well controlled with medication. No personal or family history of SPS or cancers was reported. Physical examination was unremarkable. Since the patient was Helicobacter pylori negative, the diagnosis of H. pylori infection-related GC was excluded. The patient underwent colonoscopy and found multiple flat and sessile polyps located throughout different segments of the colon and ranging from 5 to 20 mm in diameter. More than 10 polyps were removed and pathological examination confirmed most polyps to be sessile serrated lesions (SSLs) and 4 as tubular adenoma, all without severe dysplasia. The diagnosis of SPS was established. Half a year later, a gastroscopy was performed during the postoperative re-examination to screen for other lesions of the upper gastrointestinal tract. An elevated lesion was detected in the anterior wall of the gastric antrum. Total genome DNA from peripheral blood was extracted using the cetrimonium bromide/sodium dodecyl sulfate method. Gene libraries were constructed and paired-end sequencing was performed using the Illumina® HiSeq platform. Statistics was mapped with a reference genome using Burrows-Wheeler Alignment software (parameters: mem-t4-k32-M) and the duplicates were removed by Picard. Individual single nucleotide polymorphism (SNP) variations were detected using the Genome Analysis Toolkit. Subsequently, annotation of the detected SNPs was performed using SnpEff. To explore the molecular characteristics of the patient, sequencing analysis was performed. Exome sequencing identified 3111 nonsynonymous single nucleotide variants in the exon region. These genes were filtered by the mutation data in ClinVar, COSMIC v90 and previous genome-wide association study reports. Five GC-associated variants (methylenetetrahydrofolate reductase [MTHFR], metaxin 1 [MTX1], coiled-coil domain containing 6 [CCDC6], glutamate ionotropic receptor delta type subunit 1 [GRID1], and aldehyde dehydrogenase 1 [ALDH2]) were identified, as shown in Table. Additionally, a cross check for genes that has been reported as causative of SPS or relating to the serrated pathway was performed. The BRAF V600E and KRAS G12D mutations, common hotspot mutations in SPS, were not found.