ClinVar Genomic variation as it relates to human health

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 139 of the CDKN2A (p16INK4a) protein (p.Gly139Arg). This variant is present in population databases (rs587781733, gnomAD 0.002%). This missense change has been observed in individual(s) with melanoma (PMID: 25780468). ClinVar contains an entry for this variant (Variation ID: 216276). 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 tolerated. 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 is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with melanoma (Harland et al., 2014; Yehia et al., 2018); Published functional studies suggest no damaging effect: cell proliferation similar to wild type (Kimura et al., 2022); This variant is associated with the following publications: (PMID: 29684080, 25780468, 35001868)

BS3, PM2

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This variant replaces glycine with arginine at codon 139 of the CDKN2A (p16iNK4A) protein. Functional studies conducted in a cell proliferation assay have shown mutant protein activity comparable to wild type (PMID: 35001868). This variant has been reported in two individuals affected with melanoma (PMID: 25780468) and an individual affected with breast cancer, ovarian cancer, or pancreatic cancer (PMID: 32957588). This variant has been identified in 2/246404 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.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

The CDKN2A p.G139R variant was identified in 2 of 5858 proband chromosomes (frequency: 0.00034) from individuals with melanoma and was not identified in 2168 control chromosomes from healthy individuals (Harland_2014_PMID:25780468). The variant was identified in dbSNP (ID: rs587781733) asnd ClinVar (classified as uncertain significance by Counsyl, Color and Invitae). The variant was identified in control databases in 2 of 246404 chromosomes at a frequency of 0.000008117 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 2 of 110668 chromosomes (freq: 0.000018), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.G139 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.