ClinVar Genomic variation as it relates to human health

This missense variant replaces arginine with tryptophan at codon 99 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with multiple primary melanoma (PMID: 17218939). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This variant is also known as c.338C>T (p.Pro113Leu) in the CDKN2A (p14ARF) transcript. 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 disrupts the p.Arg99 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19260062, 20340136, 21462282, 23190892). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 483350). This missense change has been observed in individual(s) with melanoma (PMID: 16234564, 26681309). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 99 of the CDKN2A (p16INK4a) protein (p.Arg99Trp). The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant.

The p.R99W variant (also known as c.295C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 295. The arginine at codon 99 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in both sporadic and familial melanoma (Begg CB et al. J. Natl. Cancer Inst., 2005 Oct;97:1507-15; Potrony M et al. J. Am. Acad. Dermatol., 2014 Nov;71:888-95; Orlow I et al. J. Invest. Dermatol., 2007 May;127:1234-43). Structural analysis of this variant did not show a significant effect of p.R99W on CDKN2A protein stability (Rajasekaran R et al. Biochimie, 2008 Oct;90:1523-9). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.