ClinVar Genomic variation as it relates to human health

Observed in a hereditary melanoma family who also harbored a CDKN2A variant (Ile49Ser) found to segregate with cancer (Holland 1999), as well as in an individual suspected of having Lynch syndrome (Yurgelun 2015); Functional studies demonstrate that this variant does not significantly affect binding with CDKN2C or other protein interactions (Lambert 2013, Rolland 2014); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25416956, 24162924, 19888216, 11828258, 22932448, 25980754, 10398427)

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 52 of the CDK4 protein (p.Ser52Asn). This variant is present in population databases (rs760719270, gnomAD 0.004%). This missense change has been observed in individual(s) with head and neck carcinoma, melanoma, and/or ovarian cancer (PMID: 10398427, 22932448, 25980754, 34326862). ClinVar contains an entry for this variant (Variation ID: 439046). 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 CDK4 function (PMID: 24162924, 25416956). 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.S52N variant (also known as c.155G>A), located in coding exon 1 of the CDK4 gene, results from a G to A substitution at nucleotide position 155. The serine at codon 52 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in two out of four individuals from a family with hereditary melanoma, however this family is also noted to carry a CDKN2A alteration (Ile49Ser), which was detected in three of the four individuals (Holland EA et al. Genes Chromosomes Cancer. 1999 Aug;25:339-48). Although this amino acid position lies near the cyclin binding site, it is not predicted to make direct contact with D type cyclins in the crystal structure, and although some models show that this alteration may perturb binding to CDKN2C, functional studies showed that this alteration behaved like wildtype with respect to CDKN2C, CDKN1B, CDC37 and HSP90 binding (Rolland T et al. Cell. 2014 Nov;159:1212-1226; Zhong Q et al. Mol. Syst. Biol. 2009 Nov;5:321; Lambert JP et al. Nat. Methods. 2013 Dec;10:1239-45). This variant has also been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This amino acid position is highly 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: CDK4 c.155G>A (p.Ser52Asn) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251460 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.155G>A has been reported in the literature in one family affected with Melanoma (Holland_1999), however all affected members of the family also had a second (possibly) pathogenic variant (CDKN2A c.146T>G, p.Ile49Ser), which could explain the phenotype. In addition, co-occurrences with other pathogenic variants have been reported (CHEK2 c.1100delC, p.Thr367MetfsX15; in an internal LCA sample), providing supporting evidence for a benign role. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated using yeast two-hybrid assays that the variant doesn't significantly affect protein interactions (Zhong_2009, Lambert_2013, Rolland_2014). Four ClinVar submitters have assessed the variant since 2014: all submitters classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

The CDK4 c.155G>A variant is predicted to result in the amino acid substitution p.Ser52Asn. This variant was found in two out of four patients from a family with melanoma; three out of four patients also carried a variant in the CDKN2A gene (Figure 2, Holland et al. 1999. PubMed ID: 10398427). The c.155G>A variant in CDK4 was also detected in one patient undergoing Lynch syndrome testing (Yurgelun et al. 2015. PubMed ID: 25980754) and in one child with B-ALL (Zhang et al. 2015. PubMed ID: 26580448). In vitro functional characterization showed that this variant does not perturb CDK4 binding to CDKN2C (Rolland et al. 2014. PubMed ID: 25416956). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-58145346-C-T) and is interpreted as a variant of uncertain significance in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/439046/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.