ClinVar Genomic variation as it relates to human health

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 151 of the TP53 protein (p.Pro151Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 27489289; internal data). ClinVar contains an entry for this variant (Variation ID: 376640). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). This variant disrupts the p.Pro151 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7881428, 12826609, 17606709, 20522432, 25584008). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].

The p.P151R pathogenic mutation (also known as c.452C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 452. The proline at codon 151 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a family meeting Chompret criteria (Frone MN et al. JCO Precis Oncol, 2021 Nov;5:). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

c.452C>G, located in exon 5 of the TP53 gene, is predicted to result in the substitution of Proline by Arginine at codon 151, p.(Pro151Arg). It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.49) (PP3_moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At present, there is another pathogenic missense variant in the same residue, c.451C>T, p.(Pro151Ser) (PM5_supporting). It has been reported in ClinVar (1x as pathogenic, 17x as likely pathogenic) and CancerHotspots (9 somatic observations). Based on the currently available information, c.452C>G is classified as a likely pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.