ClinVar

Description

Variant summary: The CDKN2A gene encodes multiple alternative transcripts, coding for different proteins; the most well-studied are the p16 (INK4A) and the p14 (ARF) proteins. In p16 (INK4A) the variant results in c.151G>A (p.Val51Ile), causing a conservative amino acid change located in the Ankyrin repeat-containing domain with four of five in-silico tools predict a damaging effect of the variant on protein function. Alternatively, in p14 (ARF) this nucleotide change results in the formation of c.194G>A (p.Gly65Asp). An in silico study predicted that the variant has a benign effect for p16 and is possibly damaging for ARF (Yang 2005). In addition, this variant is located at the first 5' position in exon 2: 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.5e-06 in 220322 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.151G>A has been reported in the literature as a somatic variant in various tumors (e.g. Ohta 1996, COSMIC database, Jauhri_2016). However, these report(s) do not provide unequivocal conclusions about association of the germline variant with Cutaneous Malignant Melanoma. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that the variant had no damaging effect on the mouse homologue of the p16 protein (i.e. it had similar function to the WT), however, authors did not test the effect of the variant on the other affected protein, p19 ARF (the mouse homologue of p14 ARF) (Zhang 2001). Therefore these data do not allow convincing conclusions about the variant effect. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.