Submissions for variant NM_000546.6(TP53):c.766A>C (p.Thr256Pro)

dbSNP: rs587781433

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633389	SCV000754611	uncertain significance	Li-Fraumeni syndrome	2023-11-23	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 256 of the TP53 protein (p.Thr256Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteosarcoma (PMID: 25512523). ClinVar contains an entry for this variant (Variation ID: 528269). 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: 12826609, 29979965, 30224644). 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.
Ambry Genetics	RCV001026685	SCV001189115	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	clinical testing	The p.T256P variant (also known as c.766A>C), located in coding exon 6 of the TP53 gene, results from an A to C substitution at nucleotide position 766. The threonine at codon 256 is replaced by proline, an amino acid with highly similar properties. This alteration has been reported in an individual with osteosarcoma (Perry JA et al. Proc. Natl. Acad. Sci. U.S.A., 2014 Dec;111:E5564-73). 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 amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV002289933	SCV002581990	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001026685	SCV002582004	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002289933	SCV004932058	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	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].