ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.632C>T (p.Thr211Ile)

dbSNP: rs2073331490
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002022697 SCV002288486 uncertain significance Li-Fraumeni syndrome 2024-04-05 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 211 of the TP53 protein (p.Thr211Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 1503185). 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, 22710932, 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.
Mayo Clinic Laboratories, Mayo Clinic RCV003481246 SCV004224309 uncertain significance not provided 2023-06-13 criteria provided, single submitter clinical testing PP3, PM2_supporting, PS3_moderate
Myriad Genetics, Inc. RCV004046067 SCV004931874 likely pathogenic Li-Fraumeni syndrome 1 2024-02-15 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].
Ambry Genetics RCV004681393 SCV005177921 likely pathogenic Hereditary cancer-predisposing syndrome 2024-06-06 criteria provided, single submitter clinical testing The p.T211I variant (also known as c.632C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 632. The threonine at codon 211 is replaced by isoleucine, an amino acid with similar properties. 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 variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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