chr17-7674243-A-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000546.6(TP53):c.720T>A(p.Ser240Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S240N) has been classified as Pathogenic.
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.720T>A | p.Ser240Arg | missense_variant | 7/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.720T>A | p.Ser240Arg | missense_variant | 7/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2020 | This variant has not been reported in the literature in individuals with TP53-related conditions. Experimental studies have shown that this variant affects TP53 protein function (PMID: 29979965, 30224644, 12826609); whereas other studies suggest that this variant retains the ability to suppress cell growth and bind MDM2 (PMID: 12509279). This variant has been classified as a second-site suppressor mutation that potentially creates a novel DNA contact and rescues the effect of other pathogenic variants (PMID: 23863845, 17401432, 15037740). However, the clinical significance of these findings is uncertain. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 240 of the TP53 protein (p.Ser240Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 09, 2023 | The p.S240R variant (also known as c.720T>A), located in coding exon 6 of the TP53 gene, results from a T to A substitution at nucleotide position 720. The serine at codon 240 is replaced by arginine, an amino acid with dissimilar 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 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Another alteration at the same codon, p.S240G (c.718A>G), has been reported in a proband with Li-Fraumeni syndrome diagnosed with adrenocortical carcinoma at 1 year of age (Villani A et al. Lancet Oncol 2016 Sep;17(9):1295-305). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.