Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001241265 | SCV001414272 | uncertain significance | Familial melanoma | 2019-11-26 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that p.Leu65Phe in p16INK4a is likely to be tolerated. These same algorithms do not agree on the potential impact of p.Ala79Val in p14ARF (SIFT: "Tolerated"' PolyPhen-2: "Possibly damaging"; Align-GVGD: "Class C0"). These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with CDKN2A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 65 of the p16INK4a protein (p.Leu65Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. Alternatively, this sequence change replaces alanine with valine at codon 79 of the p14ARF (p.Ala79Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. |