Submissions for variant NM_000546.6(TP53):c.470T>C (p.Val157Ala)

dbSNP: rs1131691023

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492393	SCV000581132	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-08	criteria provided, single submitter	clinical testing	The p.V157A pathogenic mutation (also known as c.470T>C), located in coding exon 4 of the TP53 gene, results from a T to C substitution at nucleotide position 470. The valine at codon 157 is replaced by alanine, an amino acid with similar properties. This variant has been reported in multiple individuals with features consistent with Li-Fraumeni syndrome (Parsons DW et al. JAMA Oncol, 2016 May;2:616-624; Ambry internal data). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (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). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55; Ambry internal data). Another variant at the same codon, p.V157F (c.469G>T), has been detected in multiple individuals with features consistent with Li-Fraumeni syndrome (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; Azzollini J et al. Cancers (Basel), 2020 Sep;12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV002274041	SCV002559481	pathogenic	not provided	2022-03-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression activity with a dominant-negative effect (Kato et al., 2003; Giacomelli et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23810757, 30840781, 34607348, 28446506, 15510160, 26822237, 12826609, 30224644)
Genome-Nilou Lab	RCV000492393	SCV002582393	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289672	SCV002583054	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003509552	SCV004296713	uncertain significance	Li-Fraumeni syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 157 of the TP53 protein (p.Val157Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adrenocortical carcinoma (PMID: 26822237, 35306447). ClinVar contains an entry for this variant (Variation ID: 428887). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 22710932). 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.
Donald Williams Parsons Laboratory, Baylor College of Medicine	RCV000505579	SCV000599967	likely pathogenic	Adrenal cortex carcinoma	2013-05-29	no assertion criteria provided	research	Likely pathogenicity based on finding it once in this study in a 5-year-old male with adrenocortical carcinoma and 2nd degree relatives on both sides of the family with early-onset adult cancer.