17-7673793-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.827C>G(p.Ala276Gly) variant causes a missense change involving the alteration of a 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A276D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.827C>G | p.Ala276Gly | missense_variant | 8/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.827C>G | p.Ala276Gly | missense_variant | 8/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 03, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 276 of the TP53 protein (p.Ala276Gly). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 185319). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (external communication). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 13, 2022 | The p.A276G pathogenic mutation (also known as c.827C>G), located in coding exon 7 of the TP53 gene, results from a C to G substitution at nucleotide position 827. The alanine at codon 276 is replaced by glycine, an amino acid with similar properties. This variant has been determined to be the result of a de novo mutation in an individual with three primary tumors by the age of 28, including an adrenocortical carcinoma (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at