Submissions for variant NM_000546.6(TP53):c.752T>C (p.Ile251Thr)

dbSNP: rs730882027

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506798	SCV000602277	uncertain significance	not specified	2016-11-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379962	SCV001577878	likely pathogenic	Li-Fraumeni syndrome	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 251 of the TP53 protein (p.Ile251Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 439320). 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). 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	RCV001755753	SCV002007792	uncertain significance	not provided	2020-04-03	criteria provided, single submitter	clinical testing	Published functional studies are inconclusive: conflicting results in both transactivation and growth suppression assays (Kato 2003, Shiraishi 2004, Kotler 2018, Giacomelli 2018); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with HER2-negative breast cancer (Sheng 2019); This variant is associated with the following publications: (PMID: 22768918, 28724667, 30840781, 22319594, 14559903, 17981789, 31119730, 28199989, 30224644, 29979965)
Ambry Genetics	RCV002395222	SCV002669138	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-15	criteria provided, single submitter	clinical testing	The p.I251T pathogenic mutation (also known as c.752T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 752. The isoleucine at codon 251 is replaced by threonine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: 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 (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration was detected in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119). Further, another alteration at this codon (p.I251L) has been reported in the literature in one family with Li-Fraumeni syndrome (Wu CC et al. Hum. Genet. 2011 Jun; 129(6):663-73). This amino acid position is highly conserved in available vertebrate species. 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.