Abstract Introduction/Objective Myelodysplastic Syndrome (MDS) is a family of clonal hematopoietic malignancies found frequently in the seventh and eight decades, supporting that aging and acquired somatic mutations drive development of the disease. Without a cure, the prognosis is poor. Patient consideration for bone marrow transplantation remains low (<5%), and enrollment in clinical trials is slightly better (25%). Information regarding MDS-specific whole genome sequencing, a prognostic prediction system, and overall survival is limited and may be beneficial in developing curative therapies. Hence, we aimed to analyze the genomic profile, epidemiology, and overall survival of MDS. Methods/Case Report We utilized cBioPortal cancer genomics [The Cancer Genome Atlas (TCGA) PanCancer Atlas, TCGA Firehose Legacy, and TCGA Nature 2013] to study the mutations associated with MDS. Epidemiological characteristics and genetic profiles available on cBioportal were evaluated. Gene mutations with the most statistically significant, shortest overall survival and survival in days were used for the gene query, and survival rate with the common mutations was calculated. Logrank test and Kaplan–Meier estimators were used in analyzing the survival function. Patients with two or more overlapping mutations were excluded. Results (if a Case Study enter NA) We identified 7,554 patients with MDS out of which 2,852 had a primary MDS. There were 3,323 patients who had gender and age data available. 26.5% were male, and most patients (600) were between the ages of 70-75 years. 1573 (20.8%) were alive and 1600 (21.2%) were deceased. The common mutations associated with reduced survival were ASXL1, NPM1, FLT3, TET2, SF3B1, SRSF2, STAG2, RUNX1, TP53. Median survival of patients with these mutations was 32.02, 27.32, 25.97, 64.21, 80.94, 46.82, 44.28, 16.21, and 10.52 months respectively in comparison with the unaltered mutation group (68.68) (p < 0.0001). Survival was lowest amongst TP53 10.52 months and RUNX1 16.21 months. Leukemia free survival with ASXL1, NPM1, FLT3, TET2, SF3B1, SRSF2, STAG2, RUNX1, and TP53 mutations was 27.88, 13.02, 23.44, 56.52, 79.96, 37.32, 24.89, 14.86, and 9.44 months respectfully in comparison to the unaltered mutation group (68.68) (p < 0.0001). Conclusion Our study found that TP53 and RUNX1 genes were associated with the worst prognosis in MDS with median survival of 10.52 and 16.21 months, respectively. This study may provide insight for genetic predictors and targeted therapies for MDS, as well as provide better understanding of patient prognosis.