ClinVar Genomic variation as it relates to human health

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. This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 112 of the CDKN2A (p16INK4a) protein (p.Arg112Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma (PMID: 10398427, 12072543, 16307646, 16896043, 16905682, 17047042, 21462282, 22841127). It has also been observed to segregate with disease in related individuals. This variant is also known as c.377C>G (p.Pro126Arg) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 233484). 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. Experimental studies have shown that this variant affects protein function, which reduces binding to CDK4 and alters sub-cellular localization in vitro (PMID: 11518711, 20340136), but has conflicting results on cell-cycle arrest (PMID: 21462282, 12606942). For these reasons, this variant has been classified as Pathogenic. While the evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, its association with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear.

The p.R112G variant (also known as c.334C>G), located in coding exon 2 of the CDKN2A gene, results from a C to G substitution at nucleotide position 334. The arginine at codon 112 is replaced by glycine, an amino acid with dissimilar properties. Of note, this alteration is also known as c.377C>G (p.P126R) in the p14(ARF) isoform. This variant was detected in a high-risk Australian melanoma family and segregated with disease in 3/3 affected individuals tested, including 2 relatives diagnosed in their twenties (Holland EA et al, Genes Chromosomes Cancer 1999 Aug; 25(4):339-48). This variant was reported in individuals with features consistent with Melanoma-pancreatic cancer syndrome (Ambry internal data). This alteration has also been reported in several additional melanoma families (Lang J et al. Br J Dermatol, 2005 Dec;153:1121-5; Maubec E et al. J Am Acad Dermatol, 2012 Dec;67:1257-64; Stolarova L et al. Biomedicines, 2020 Oct;8:). Functional analyses have shown p.R112G to be correlated with with decreased CDK4 binding in vivo, reduced expression, altered localization and impaired cell cycle arrest compared to wild type p16 (Rizos H et al, J. Biol. Chem. 2001 Nov; 276(44):41424-34; McKenzie HA et al. Hum Mutat, 2010 Jun;31:692-701; Miller PJ et al, Hum. Mutat. 2011 Aug; 32(8):900-11). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This missense variant replaces arginine with glycine at codon 112 of the CDKN2A (p16INK4A) protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant results in the reduced protein expression, altered subcellular localization and impaired p16INK4A binding to CDK4 (PMID: 11518711, 20340136). This variant has shown no or partial impact on the cell cycle arrest activity of the p16INK4A protein (PMID: 11518711, 12606942, 21462282). This variant has been reported in over 15 individuals and families affected with melanoma (PMID: 10398427, 12072543, 16307646, 16896043, 16905682, 17047042, 21462282, 22841127, 33050356). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.