Submissions for variant NM_000546.6(TP53):c.149T>C (p.Ile50Thr)

dbSNP: rs370502517

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000197538	SCV001737932	likely benign	Li-Fraumeni syndrome	2025-01-16	reviewed by expert panel	curation	The NM_000546.6: c.149T>C variant in TP53 is a missense variant predicted to cause substitution of Isoleucine by Threonine at amino acid 50 (p.Ile50Thr). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor: LabCorp Genetics). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor: LabCorp Genetics). This variant has an allele frequency of 0.000001239 (2/1614026 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function; however a third assay corroborating these findings was not available (BS3_Supporting not met; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = -0.0655; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, PP4, PM2_Supporting, BP4_Moderate. (Bayesian Points: -2; VCEP specifications version 2.1.0; 1/16/2025)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197538	SCV000254627	uncertain significance	Li-Fraumeni syndrome	2024-05-11	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 50 of the TP53 protein (p.Ile50Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 216464). 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 does not substantially affect TP53 function (PMID: 12826609, 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	RCV000220760	SCV000274284	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-22	criteria provided, single submitter	clinical testing	The p.I50T variant (also known as c.149T>C), located in coding exon 3 of the TP53 gene, results from a T to C substitution at nucleotide position 149. The isoleucine at codon 50 is replaced by threonine, an amino acid with similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing; this patient was diagnosed with acute lymphocytic leukemia (Zhang J et al. N. Engl. J. Med. 2015 Dec;373(24):2336-2346). This variant is in the transactivation domain of the TP53 protein and is reported to have a partial loss of transactivation capacity in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000662678	SCV000785386	uncertain significance	Li-Fraumeni syndrome 1	2017-07-19	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662678	SCV004017883	uncertain significance	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV000197538	SCV004815882	uncertain significance	Li-Fraumeni syndrome	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 50 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies have shown that this variant is partially functional in yeast transactivation assays (PMID: 12826609) and exhibited normal function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with B-lineage acute lymphoblastic leukemia (PMID: 26580448). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.