MITF E318K is a moderate melanoma allele, and the naevus count is the clue

Design

systematic review with meta-analysis of 11 retrospective case-control studies

Population

8,606 melanoma patients and 17,953 controls

Primary outcome

cancer risk associated with germline MITF variants

Effect

melanoma odds ratio 2.55 for E318K (95% CI 1.90 to 3.43); carrier frequency 2.1% versus 0.8%

Eleven retrospective case-control studies, covering 8,606 melanoma patients and 17,953 controls, were pooled to settle what germline MITF variants actually confer. The E318K variant was present in 2.1% of melanoma cases and 0.8% of controls, giving an odds ratio for melanoma of 2.55 (95% CI 1.90 to 3.43).

The signal concentrates where it would be expected. Carrier frequency reached 2.6% in people with multiple primary melanomas against 1.0% in single melanoma, with odds ratios up to 4.45 in individual studies. The phenotype most strongly enriched was a high naevus burden, more than 200 naevi, with odds ratios up to 12.4 in multiple-melanoma cohorts. There was no consistent association with age at onset or with pigmentary traits — so this is not a variant you would suspect from skin type or hair colour.

Beyond melanoma the evidence thins out. One study reported raised renal cancer risk (odds ratio 7.64) that larger cohorts did not replicate, and an association with phaeochromocytoma and paraganglioma (odds ratio 3.19) remains unconfirmed. No other MITF variant showed significant cancer risk.

For practice this places E318K alongside the other moderate-penetrance alleles rather than with CDKN2A. It does not justify extended surveillance of other organs, and it does not change what you do for a carrier beyond what a high naevus count and a personal history of multiple primaries would already demand.

• Count naevi and record multiple primaries — those, not skin type, are what should prompt genetic referral here
• Do not offer renal or adrenal surveillance to an E318K carrier on this evidence
• Explain moderate penetrance plainly: most carriers will not develop melanoma
• Keep the whole-body examination interval driven by phenotype and history rather than by the variant alone
• Extend counselling to first-degree relatives with high naevus counts

The statistics, in plain English

An odds ratio of 2.55 based on carrier frequencies of 2.1% against 0.8% means the absolute numbers stay small: most carriers will never have a melanoma, and most melanomas occur in non-carriers. The odds ratios up to 12.4 for high naevus burden come from individual cohorts rather than the pooled estimate and should be read as the strongest observations, not the summary. The non-melanoma associations rest on single unreplicated studies, which is the weakest form of evidence a meta-analysis can report.

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