- Design
- systematic review and meta-analysis of 11 retrospective case-control studies
- Population
- 8,606 melanoma patients and 17,953 controls tested for germline MITF variants
- Primary outcome
- melanoma and other cancer risk by MITF variant
- Effect
- E318K melanoma OR 2.55 (95% CI 1.90-3.43); carrier frequency 2.1% vs 0.8%; naevus burden over 200 enriched
Eleven retrospective case-control studies were pooled, covering 8,606 melanoma patients and 17,953 controls, to ask what germline MITF variants actually confer. The E318K variant was carried by 2.1% of melanoma patients and 0.8% of controls, an odds ratio of 2.55 (95% CI 1.90-3.43).
The association concentrated where you would expect a susceptibility allele to concentrate. Carrier frequency reached 2.6% in people with multiple primary melanomas against 1.0% in those with a single melanoma, with odds ratios as high as 4.45 in individual studies. Phenotypically, carriers were enriched for a high naevus burden — more than 200 naevi — with odds ratios up to 12.4 in multiple-melanoma cohorts. No consistent association appeared with age at onset or with pigmentary traits, which distinguishes this from the classic fair-skin risk alleles.
Outside melanoma the evidence thins to nothing usable. One study reported raised renal cancer risk (OR 7.64) that larger cohorts did not replicate, and an association with phaeochromocytoma or paraganglioma (OR 3.19) remains unconfirmed. No other MITF variant showed significant cancer risk.
So the clinical shape is narrow: E318K is a moderate-penetrance melanoma allele, most relevant to the patient with multiple primaries and a very high naevus count, and it does not currently justify extending surveillance to other organs. Germline melanoma panel testing is not widely available or funded in India, and the phenotype — many naevi, more than one primary — remains the thing that should drive surveillance intensity whether or not a variant is identified.
- Base surveillance intensity on phenotype — multiple primaries and a very high naevus count — rather than waiting for a genetic result
- Where MITF E318K is found, treat it as a moderate-penetrance melanoma allele, not a high-risk syndrome
- Do not extend surveillance to kidney, adrenal or other organs on this evidence; the non-melanoma associations were unreplicated
- Count naevi and record the number; carriers were enriched above 200 naevi
- Do not expect carriers to be fair-skinned or young at onset — neither association held up
Why it matters
Panel results are increasingly arriving in melanoma clinics, and this one changes the naevus count conversation rather than the surveillance organ list.
Don't overread it
Retrospective case-control data cannot give an individual's lifetime risk, and the non-melanoma cancer signals came from single unreplicated studies.
The statistics, in plain English
An odds ratio of 2.55 with an interval of 1.90 to 3.43 is a secure but moderate association — it does not sit near the tenfold risks of a high-penetrance gene. The very large odds ratios quoted (4.45, 12.4, 7.64) come from individual studies rather than the pooled analysis, which is why they are so much bigger and so much less reliable; single-study extremes in a meta-analysis usually shrink when replicated. Because the carrier frequency is low in both groups (2.1% against 0.8%), these ratios rest on relatively few carriers, and all 11 studies were retrospective case-control designs, which are prone to selection of the most striking families.
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