MITF c.952G>A (p.E318K) (the variant nomenclature is reported by MANE Plus Clinical as MITF NM_000248.4:c.952G>A (p.E318K) and MANE Select as MITF NM_001354604.2:c.1273G>A (p.E425K)) is a moderate genetic risk factor for melanoma but the scientific community continues to debate whether it is associated with the risk of renal cell carcinoma (RCC). This manuscript advances this debate by bringing together previous research reports with new research findings. We find that further evidence that meets the standard for inclusion in clinical variant curation is required to classify this variant. It remains imperative to resolve the possible association of MITF c.952G>A with RCC risk so that it can be used clinically to support genetic counselling and cancer risk management.

MITF c.952G>A is possibly a genetic risk factor for RCC. Bertolotto et al 1 first reported that this variant increased the risk of RCC (OR 5.19, 95% CI 1.37 to 16.87), melanoma (OR 4.78, 95% CI 2.05 to 11.75) and both RCC and melanoma (OR 14.46, 95% CI 3.74 to 48.04) in a French clinic-based series enriched for genetic predisposition. The identified carrier frequency of c.952G>A was 0.6% in a control group (n=10/1659), 2.8% in those affected with melanoma (n=17/603), 3% in those affected with RCC (n=5/164) and 8% in those affected with both melanoma and RCC (n=5/62).1 Hubert et al 2 also observed a high frequency of carriers (7.2%, n=9/125) in a French clinic-based series of individuals with both melanoma and RCC. …