The study investigates the role of methylglyoxal (MGO), a glycolytic metabolite, in bypassing Knudson's "two-hit" requirement for tumor suppression by BRCA2. MGO transiently inactivates BRCA2 function, leading to genome-wide single-base substitution (SBS) mutations in monoallelic *BRCA2* mutant cells. This effect is more pronounced in cells with germline monoallelic *BRCA2* mutations, which are more sensitive to MGO-induced haploinsufficiency. The accumulation of MGO, often associated with metabolic disorders or dietary factors, can trigger BRCA2 proteolysis and disable its tumor suppressive functions in DNA repair and replication. Intermittent exposure to MGO over prolonged periods sufficient to induce episodes of genome-wide SBS mutagenesis without permanent BRCA2 inactivation. This mechanism links metabolic reprogramming, metabolic disorders, or diet to early steps in carcinogenesis, potentially contributing to cancer genome evolution. The findings suggest that Knudson's two-hit requirement for tumor suppression may be fulfilled through a distinct, short-lived metabolic mechanism, in addition to established routes for long-term tumor suppressor gene inactivation.The study investigates the role of methylglyoxal (MGO), a glycolytic metabolite, in bypassing Knudson's "two-hit" requirement for tumor suppression by BRCA2. MGO transiently inactivates BRCA2 function, leading to genome-wide single-base substitution (SBS) mutations in monoallelic *BRCA2* mutant cells. This effect is more pronounced in cells with germline monoallelic *BRCA2* mutations, which are more sensitive to MGO-induced haploinsufficiency. The accumulation of MGO, often associated with metabolic disorders or dietary factors, can trigger BRCA2 proteolysis and disable its tumor suppressive functions in DNA repair and replication. Intermittent exposure to MGO over prolonged periods sufficient to induce episodes of genome-wide SBS mutagenesis without permanent BRCA2 inactivation. This mechanism links metabolic reprogramming, metabolic disorders, or diet to early steps in carcinogenesis, potentially contributing to cancer genome evolution. The findings suggest that Knudson's two-hit requirement for tumor suppression may be fulfilled through a distinct, short-lived metabolic mechanism, in addition to established routes for long-term tumor suppressor gene inactivation.