ClinVar Miner

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

dbSNP: rs370502517
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000662678 SCV001737932 likely benign Li-Fraumeni syndrome 1 2021-04-02 reviewed by expert panel curation This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). Transactivation assays show a partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). In summary, TP53 c.149T>C (p.Ile50Thr) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, BS3_Supporting, BP4.
Invitae RCV000197538 SCV000254627 uncertain significance Li-Fraumeni syndrome 2024-01-24 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.

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