ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.149T>C (p.Ile50Thr) (rs370502517)

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Total submissions: 4
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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 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 50 of the TP53 protein (p.Ile50Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with acute lymphoblastic leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 216464). An experimental study in yeast has shown that this variant partially impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). 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 2019-08-29 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

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