ClinVar Genomic variation as it relates to human health

Variant summary: The c.292C>T (p.His98Tyr) in CDKN2A gene is a missense change that involves a mildly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. Despite that two independent studies have confirmed that H98Ywas acting not significantly different from wild-type when was tested in growth binding and phosphorylation assays. Both research groups agreed that H98y may represent a rare functional variant rather than causative mutation. The variant is absent from the control population dataset of ExAC. The variant was identified in a glioma tumor sample, but has not been reported by any reputable database/clinical laboratory. Taking together, the variant was classified as VUS until undeniable evidence confirming neutrality become available.

This variant is denoted CDKN2A c.292C>T at the cDNA level, p.His98Tyr (H98Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAC>TAC). This variant is associated with growth suppression, RB phosphorylation, and CDK4 and CDK6 binding similar to wild type (Arap 1997, Ruas 1999, Miller 2011). CDKN2A His98Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDKN2A His98Tyr occurs at a position that is conserved in mammals and is located within the ANK3 domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CDKN2A His98Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.

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 histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 98 of the CDKN2A (p16INK4a) protein (p.His98Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. This variant is also known as c.335C>T (p.Ala112Val) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 419560). 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 missense change does not substantially affect CDKN2A (p16INK4a) function (PMID: 9053859, 21462282). 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.H98Y variant (also known as c.292C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 292. The histidine at codon 98 is replaced by tyrosine, an amino acid with similar properties. This alteration has been identified in glioblastoma cell line and functional studies have demonstrated the CDK4/CDK6 binding, growth suppression and effect on cell cycle arrest are similar to wild type (Arap W et al. Oncogene, 1997 Feb;14:603-9; Ruas M et al. Oncogene, 1999 Sep;18:5423-34). This amino acid position is 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.