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The MITF E318K variant has been associated with melanoma risk, while risk associated with other variants or of other cancers remains uncertain. We performed a systematic review with meta-analysis of 11 retrospective case-control studies to evaluate cancer risks associated with germline MITF variants. Across 8,606 melanoma patients and 17,953 controls, the E318K variant was detected in 2.1% and 0.8% of individuals, respectively, corresponding to a significantly increased melanoma risk (OR 2.55, 95% CI 1.90-3.43). The association was stronger in patients with multiple primary melanomas, with carrier frequencies up to 2.6% compared to 1.0% in single melanoma cases and ORs reaching 4.45 in individual studies. Phenotypic analyses showed enrichment of high nevus burden (> 200 nevi), with ORs up to 12.4 in multiple melanoma cohorts. No consistent association with age at onset or pigmentary traits was observed. Evidence for non-melanoma cancers was limited and heterogeneous: a single study reported increased renal cancer risk (OR 7.64), whereas larger cohorts failed to replicate this finding; an association with pheochromocytoma/paraganglioma was observed (OR 3.19) but lacks confirmation. No other MITF variants demonstrated significant cancer risk. These findings support MITF E318K as a moderate-penetrance melanoma susceptibility allele, particularly associated with multiple primary melanomas.