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Cancer genetics
Brief communication
Is renal cell carcinoma associated with MITF c.952G>A (p.E318K)?
  1. Philip Harraka1,
  2. Fiona Bruinsma2,3,
  3. Tu Nguyen-Dumont4,5,
  4. Susan Jordan6,
  5. Graham G. Giles2,
  6. Ingrid M Winship7,8,
  7. Kathy Tucker9,
  8. Melissa C. Southey1,2,5
  1. 1 Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, Australia
  2. 2 Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
  3. 3 Burnet Institute, Melbourne, Victoria, Australia
  4. 4 Clinical Genomics, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia
  5. 5 Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia
  6. 6 School of Public Health, The University of Queensland, Brisbane, Queensland, Australia
  7. 7 Genomic Medicine, The Royal Melbourne Hospital, Parkville, Victoria, Australia
  8. 8 Department of Medicine, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia
  9. 9 Hereditary Cancer Service, Prince of Wales Hospital NCCC, Randwick, New South Wales, Australia
  1. Correspondence to Professor Melissa C. Southey; melissa.southey{at}monash.edu

https://doi.org/10.1136/jmg-2024-109984

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    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. …

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    Footnotes

    • Contributors PH and MS: concept and design; TN-D, FB, SJ, GG, IMW, KT and MS: funding; PH, FB, TN-D, SJ, GG, IMW, KT and MS: acquisition of data; PH, TN-D, SJ and MS: analysis and interpretation; PH and MS: drafting of manuscript; PH, FB, TN-D, SJ, GG, IMW, KT and MS: approval of final version of manuscript. MCS is the guarantor.

    • Funding This work was supported by the Victorian Cancer Agency (Grant number EO109_36); The National Health and Medical Research Council (GNT1074383, GNT1025879, GNT2011329); Cancer Council Victoria (GNT1066612); TN-D is a recipient of a Victorian Cancer Agency Mid-Career Research Fellowship (MCRF21029); MCS is a recipient of an NHMRC L3 Investigator Fellowship (GNT2017325).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.