17-7674253-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000546.6(TP53):c.710T>C(p.Met237Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461704Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727164
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
This missense variant replaces methionine with threonine at codon 237 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have been inconclusive about the variant impact on TP53 protein function. The mutant protein has been reported to be partially functional in IARC yeast transactivation assays (IARC database and PMID: 12826609) but functional or inconclusive in human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in an adult individual affected with acute lymphoblastic leukemia (PMID: 2340332). 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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The p.M237T variant (also known as c.710T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 710. The methionine at codon 237 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 partially functional transactivation in yeast-based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression but 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 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 available evidence, the clinical significance of this variant remains unclear. -
not provided Uncertain:2
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: demonstrates partially functional transactivation, no loss of growth suppression ability, and may exhibit a dominant-negative effect (Kato et al., 2003; Giacomelli et al., 2018; Kotler et al., 2018); This variant is associated with the following publications: (PMID: 12826609, 15510160, 30224644, 29979965) -
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Li-Fraumeni syndrome 1 Uncertain:1
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Li-Fraumeni syndrome Uncertain:1
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 237 of the TP53 protein (p.Met237Thr). 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: 481069). 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. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at