• Genetics, Medical
• Genetic Research
• Molecular Epidemiology

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.

Since 2017, multiple submissions to ClinVar have classified this variant as pathogenic or likely pathogenic for melanoma (SCV000696089.4, SCV004192590.1). Despite the published association with the risk of RCC, classification of this variant for RCC predisposition, and subsequent provision of genetic counselling, is complicated by the carrier frequency of c.952G>A in reference databases, the lack of association with family history, and the diverse clinical features of RCC in carriers of this variant.

Our laboratory recently investigated a series of RCC cases from the population-based component of the Consortium for the Investigation of Renal Malignancies (CONFIRM)3 and identified the carrier frequency of c.952G>A to be 0.5% (n=5/1029) (unpublished data). This is consistent with findings from Nguyen et al 4 and Yngvadottir et al 5, who investigated a series of RCC cases that had previously undergone sequencing with, respectively, a commercial diagnostic laboratory or as part of the 100 000 Genomes Project, and identified the carrier frequency of this variant to be 0.7% (n=9/1235; n=10/1336, respectively). Together with Bertolotto et al 1, the estimated frequency of c.952G>A carriers in RCC ranges from 0.5% to 3%.^{4 5} However, this is no higher than the carrier frequency in reference databases (0.5% in non-Finnish Europeans in gnomAD v3.1.2 non-cancer) which complicates the curation of this variant. Similarly, other published research did not identify an association between c.952G>A and RCC. For example, Guhan et al 6 reported a carrier frequency of 0.8% in individuals with RCC (n=1/123) from the TCGA sporadic cancer dataset but did not observe an association with disease (p=0.507), possibly due to the small sample size.

Data related to the clinical features of the RCC arising in c.952G>A carriers are currently lacking. Germline gene panel sequencing involving 1304 Australian RCC cases (1029 from the CONFIRM population-based series reported above) identified six carriers of c.952G>A. Five of these (83%) were men, and the average age at diagnosis was 62±15 years (SD). Three of the six carriers reported a personal or family history of melanoma, but none reported a first-degree or second-degree relative with kidney cancer. Tumour subtypes were available for five of these carriers and included three men with clear cell RCC (one diagnosed in his 60s and two in their 70s), one man with papillary RCC (diagnosed in his 60s) and one woman with RCC, a subtype not known (diagnosed in her 70s); the sixth was a man in his 30s with RCC of unknown histology. This variable histology was also reported by Lang and colleagues.7

While c.952G>A has been observed to segregate with melanoma in families,1 most cases of RCC with c.952G>A do not report a family history of RCC. A study of RCC by Nguyen et al 4 identified nine carriers of c.952G>A, most of whom were younger than 45 years (median age 39, range 35–72). However, only 2/8 (22%, one missing) reported a family history of kidney cancer. Lang et al 7 reported a man in his 40s with RCC who was a carrier and whose father also had RCC (carrier status unknown). In our panel testing, five of six carriers of c.952G>A were diagnosed at 60 years of age or over, and none of them reported a family history of kidney cancer.

Functional studies have demonstrated that p.E318K impairs the post-translational addition of a covalently bound SUMO protein at amino acid K316 which has a gain-of-function effect by altering promoter occupancy and expression of many MITF-target genes.1 For melanoma, this variant may predispose to disease by inhibiting BRAF V600E oncogene-induced senescence and promoting naevus development.8 For RCC, investigation of a VHL-deficient RCC cell line indicates that this variant alters the expression of genes involved in cell growth and division and inflammation and that the mutation is associated with increased cell migration and invasion.1 A study investigating MITF knockdown and overexpression in human clear cell RCC cell lines indicates that MITF regulates cell motility and invasion through the RhoA/YAP signalling pathway.9 Although there is a plausible connection to cancer biology, the mechanism by which p.E318K might predispose to RCC has not been established.

To understand if MITF c.952G>A has clinical relevance to RCC management, larger studies, including family-based studies, in ethnically diverse populations are needed to validate the association between this variant and RCC risk. Once the clinical and functional relevance of this variant is clarified, research to address the multitude of biological pathways that may be disrupted by this variant is warranted to enable better treatment and management of carriers with RCC.