Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the highly aggressive and most common undifferentiated ovarian malignancy in women under 40 years of age. We performed exome sequencing using three families with SCCOHT and identified segregating deleterious germline mutations in gene SMARCA4 in all of them. This chromatin-remodelling gene and the related SMARCB1 gene, have been previously reported in almost all atypical teratoid/rhabdoid tumours (ATRTs). Additional sequencing of paired, formalin-fixed paraffin-embedded tumor and normal tissue indicated the complete loss of SMARCA4 in all 17 cases we studied. Remarkably, we did not observe any somatic, driving mutations other than SMARCA4. Even though SCCOHT rises in the ovary, the mutation rate of SCCOHT is significantly lower than serious ovarian cancer, but similar to ATRT. Moreover, as most ovarian tumors are aneuploidy, genome-wide allelic imbalance analysis showed that the genome of SCCOHT and ATRT are extremely simple. Large-scale copy number changes in SCCOHT have only been observed in the region result in SMARCA4 loss of heterozygosity. Furthermore, we suggest that SCCOHT tumors have distinct global methylation profiles. Taken together, our findings revealed SMARCA4 alterations as the major cause of SCCOHT, which could lead to new treatment approach that is different from other types of ovarian cancers.