ClinVar Genomic variation as it relates to human health

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate protein levels and phosphorylation levels of CDK4 and Rb proteins comparable to wild-type (Li et al., 2022); This variant is associated with the following publications: (PMID: 26104880, 8573142, 27756164, 30857943, 27960642, 18519632, 16818274, 9166859, 28765326, 7718873, 34369425, 11511321, 30395287)

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 138 of the CDKN2A (p16INK4a) protein (p.Arg138Gly). This variant is present in population databases (rs145012438, gnomAD 0.0009%). This missense change has been observed in individual(s) with dysplastic nevi that did not have a personal and family history of melanoma and acute lymphoblastic leukaemia (PMID: 11511321, 26104880). ClinVar contains an entry for this variant (Variation ID: 233990). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect CDKN2A (p16INK4a) function (PMID: 34369425). 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.

The p.R138G variant (also known as c.412A>G), located in coding exon 2 of the CDKN2A gene, results from an A to G substitution at nucleotide position 412. The arginine at codon 138 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in an individual with acute lymphoblastic leukemia (Xu H et al. Nat Commun, 2015 Jun;6:7553). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Variant summary: CDKN2A c.412A>G (p.Arg138Gly) results in a non-conservative amino acid change located in the ANK repeat 4 (CKB) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246242 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance c.412A>G has been reported in the literature in an individual with benign nevi, who had no personal or family history of melanoma (Welch_2001), and was also reported in a child affected with acute lymphoblastic leukemia, however it was also found in controls (Xu_2015). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. At least one publication reports R138G suppresses IL3-independent growth similar to wild-type in BCR-ABL1-expressing cells in culture (Li_2022). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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 138 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). A functional study has shown that this variant does not alter CDKN2A (p16INK4A) protein function as determined by cell growth assay and its effect on CDK4/6-RB-E2F2 signaling pathway (PMID: 34369425). This variant has been reported in individuals affected with childhood-onset acute lymphoblastic leukemia (PMID: 26104880) and in an individual affected with melanocytic nevi without personal or a family history of melanoma (PMID: 11511321). This variant has been identified in 2/246242 chromosomes 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.