ClinVar Genomic variation as it relates to human health

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 95 of the CDKN1B protein (p.Pro95Ser). This variant is present in population databases (rs188579132, gnomAD 0.01%). This missense change has been observed in individual(s) with multiple neoplasia type 1 and Zollinger-Ellison syndrome (PMID: 19141585). ClinVar contains an entry for this variant (Variation ID: 404265). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CDKN1B function (PMID: 19141585). 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.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with multiple endocrine neoplasia type 1 and was shown to impair binding to GRB2 (Agarwal et al., 2009); This variant is associated with the following publications: (PMID: 24819502, 20824794, 30065701, 22584700, 28824003, 34426522, 31980526, 19141585)

In the published literature, the variant has been reported in an individuals with Zollinger-Ellison Syndrome (PMID: 19141585 (2009) and multiple endocrine neoplasia (PMID: 31980526 (2020)). A functional study found that this variant reduced binding activity (PMID: 19141585 (2009)). The frequency of this variant in the general population, 0.00014 (18/128704 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.

The p.P95S variant (also known as c.283C>T), located in coding exon 1 of the CDKN1B gene, results from a C to T substitution at nucleotide position 283. The proline at codon 95 is replaced by serine, an amino acid with similar properties. This alteration was detected in one individual with features of Multiple Endocrine Neoplasia Type 1 syndrome, including hyperparathyroidism and Zollinger-Ellison syndrome (Agarwal SK et al. J. Clin. Endocrinol. Metab., 2009 May;94:1826-34). This amino acid position is not 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.

The CDKN1B p.P95S variant was identified in one individual with Zollinger-Ellison syndrome (Agarwal_2009_PMID: 19141585). The variant was not identified in COSMIC but was identified in dbSNP (ID: rs188579132) and ClinVar (classified as uncertain significance by Ambry Genetics and Invitae). The variant was identified in control databases in 23 of 281634 chromosomes at a frequency of 0.00008167, and was observed at the highest frequency in the European (non-Finnish) population in 18 of 128704 chromosomes (freq: 0.0001399) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.P95 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Functional analysis shows that this variant results in reduced protein binding activity (Agarwal_2009_PMID: 19141585). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) 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.