Genome stability is maintained by a DNA damage repair (DDR) system composed of multiple DNA repair pathways with hundreds of genes involved. Through coordinative action of different genes, each pathway repairs a given type(s) of DNA damage. However, DDR genes are prone to germline variation. A part of deleterious variation can be pathogenic in damaging function of the affected DDR genes, letting the damaged DNA unrepaired, leading to genome instability and high risk of diseases, particularly, cancer. Knowledge for the origin of DDR pathogenic variation is essential in understanding the biological basis of DDR variation and human diseases. In our study, we applied a combined phylogenetic and archaeological approach to trace the origin of germline pathogenic variants in 169 DDR genes in modern humans. We observed no sharing of DDR pathogenic variation in modern humans with non-human vertebrate species following the evolution tree, therefore, rejected cross-species conservation as the origin for human DDR pathogenic variation. However, we observed the presence of DDR variants in ancient humans dated mostly within the last 10,000 years, indicating that DDR pathogenic variants in modern humans arose during recent human history. We further observed a similar distribution pattern of DDR variation between modern and ancient humans as represented by the high prevalence of pathogenic variation in ATM, BRCA1 and BRCA2 in both ancient and modern humans, suggesting the beneficial potential of the pathogenic variants in these genes. We also identified several pathogenic variants in ATM, BRCA2 and CHEK2 shared between modern humans and Neanderthals, suggesting that the extinct hominins may contribute to cancer predisposition in modern humans. Our study provides a foundation to understand the roles of genetic predisposition in disease risk in modern humans.