Submissions for variant NM_000546.6(TP53):c.428T>G (p.Val143Gly)

dbSNP: rs1555526241

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000562247	SCV000675341	uncertain significance	Hereditary cancer-predisposing syndrome	2016-11-28	criteria provided, single submitter	clinical testing	The p.V143G variant (also known as c.428T>G), located in coding exon 4 of the TP53 gene, results from a T to G substitution at nucleotide position 428. The valine at codon 143 is replaced by glycine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and predicted to affect several p53 isoforms (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526919	SCV003337858	likely pathogenic	Li-Fraumeni syndrome	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 143 of the TP53 protein (p.Val143Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni Syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 486556). 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%. This variant disrupts the p.Val143 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 19701813, 23469205, 25318593, 29070607, 29979965, 30224644, 33178583). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx	RCV004719887	SCV005325330	likely pathogenic	not provided	2024-03-06	criteria provided, single submitter	clinical testing	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: 29979965, 12826609, 30224644, 15510160)