ClinVar Genomic variation as it relates to human health

The p.N239S variant (also known as c.716A>G), located in coding exon 6 of the TP53 gene, results from an A to G substitution at nucleotide position 716. The asparagine at codon 239 is replaced by serine, an amino acid with highly similar properties. This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity, dominant negative effect and predicted to affect several p53 isoforms in yeast-based assays (IARC TP53 database; Han Z et al. Arthritis Rheum. 1999 Jun; 42(6):1088-92; Robert V et al. Carcinogenesis 2000 Apr; 21(4):563-5; Campomenosi P et al. Oncogene 2001 Jun; 20(27):3573-9; Monti P et al. Oncogene 2002 Mar; 21(11):1641-8; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Dearth LR et al. Carcinogenesis 2007 Feb; 28(2):289-98). The asparagine at position 239 is in direct contact with the DNA helix and is known to bind to DNA helices; the loss of asparagine appears to result in reduced plasticity of the DNA-binding loops (Jia S et al. Int J Biol Sci. 2012;8(5):596-605). Based on internal structural analysis, the p.N239S alteration sits at the interface between TP53 and DNA and is anticipated to result in the loss of a sidechain with a specific functional role (Cho Y et al. Science 1994 Jul 15;265(5170):346-55). In addition, studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity, and dominant-negative effect (Han et al., 1999; Kato et al., 2003; Dearth et al., 2007; Jia et al., 2012; Kotler et al., 2018; Giacomelli et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30123427, 29312620, 32066498, 26425688, 15510160, 12826609, 29979965, 30224644, 23780408, 31748977, 11429705, 11896595, 10366100, 34540698, 10753186, 16861262, 22553460, 34298704)

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 239 of the TP53 protein (p.Asn239Ser). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 22553460, 29979965, 30224644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 376637). This missense change has been observed in individuals with breast cancer (PMID: 31748977; Invitae). This variant is not present in population databases (gnomAD no frequency).

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 28949402, 30107044].