The frequency of heritable pathogenic variant in the CDKN2A gene in unselected individuals with cutaneous melanoma is low (<1%) in Australia.r Heritable de novo pathogenic variants in the CDKN2A gene are rare.
The frequency of heritable pathogenic variants in the CDKN2A gene (affecting p16INK4A and/or p14ARF proteins) has been evaluated internationally by the GenoMEL Consortium, and its multivariate predictive model now replaces the previous MELPREDICT model developed in the US and Netherlands. The GenoMELPREDICT model performs well in Australian data, since one third of the dataset used to derive it came from Australian melanoma families with three or more cases.
Cases of uveal (internal eye) melanoma are not associated with CDKN2A pathogenic variants and should not be counted.
||Probability of detecting a heritable pathogenic variant**
|Person with 1 CMM*, diagnosed under aged 40 with no family history of CMM
|Person with ≥2 CMMs, unselected for family history
|Person with 1 CMM at age 40, part of a cluster of 3 or more cases in first and second degree blood relatives
|Person with 3 CMMs, first diagnosed aged 40, part of a cluster of 3 or more cases in first and second degree blood relatives
|Patient has a first or second degree relative with documented pathogenic variant
||Up to 50%
*CMM = cutaneous malignant melanoma (includes melanoma in-situ or invasive malignant melanoma of the skin)
**Data from Australian populations
***Probability of detecting a heritable pathogenic variant using four factor GenoMELPREDICT. The probability of detecting a heritable CDKN2A pathogenic variant is also modestly inversely correlated with the underlying population risk (incidence) of cutaneous melanoma. However, GenoMELPREDICT performs equally well in Australian families with three or more cases as in European families, where incidence rates are much lower than in Australia. Note also that the GenoMEL dataset includes no Australian families with fewer than three cases, and the predictions of the model for such families in Australia are likely to be inflated.