Submissions for variant NM_000546.6(TP53):c.428T>C (p.Val143Ala)

dbSNP: rs1555526241

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000991143	SCV001142543	pathogenic	Li-Fraumeni syndrome	2024-08-05	reviewed by expert panel	curation	The NM_000546.6: c.428T>C variant in TP53 is a missense variant predicted to cause substitution of Valine by Alanine at amino acid 143 (p.Val143Ala). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with an LFS-associated cancer totaling 6 phenotype points (PS2; PMID: 19701813, 25318593). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.1806; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of >15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has 7 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot critical functional domain by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PM2_Supporting, PS3, PP3, PM1_Supporting. (Bayesian Points: 11; VCEP specifications version 2.0; 7/24/2024).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000991143	SCV002236013	pathogenic	Li-Fraumeni syndrome	2022-10-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 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: 804214). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 19701813, 25318593, 29070607). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 143 of the TP53 protein (p.Val143Ala).
Myriad Genetics, Inc.	RCV004030120	SCV004933938	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-13	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8458321, 8013454, 10435620]. This variant is expected to disrupt protein structure [17015838].
Ambry Genetics	RCV005286262	SCV005951593	pathogenic	Hereditary cancer-predisposing syndrome	2025-01-08	criteria provided, single submitter	clinical testing	The p.V143A pathogenic mutation (also known as c.428T>C), located in coding exon 4 of the TP53 gene, results from a T to C substitution at nucleotide position 428. The valine at codon 143 is replaced by alanine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with Li-Fraumeni syndrome; in at least one individual, it was reported to be de novo or the result of germline mosaicism (Ko JH et al. Eur J Pediatr, 2010 Apr;169:501-4; Ariffin H et al. Clin Genet, 2015 Nov;88:450-5). 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 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 U S A, 2003 Jul;100:8424-9). Other variant(s) at the same codon, p.V143M (c.427G>A), have been identified in individual(s) with features consistent with Li Fraumeni syndrome (Gambale A et al. Clin. Genet. 2019 Oct;96:359-365). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.