chr17-7673794-C-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000546.6(TP53):c.826G>C(p.Ala276Pro) 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 Conflicting classifications of pathogenicity (no stars). 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 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.826G>C | p.Ala276Pro | missense_variant | 8/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.826G>C | p.Ala276Pro | missense_variant | 8/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461852Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727224
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Neoplasm of ovary Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 29, 2020 | The p.A276P pathogenic mutation (also known as c.826G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 826. The alanine at codon 276 is replaced by proline, an amino acid with highly similar properties. This alteration is located in the functionally critical and highly conserved DNA binding domain, and structural analysis reveals that a proline at this position would clash with the DNA backbone, resulting in disruption of the protein-DNA interface (Kitayner M et al. Nat. Struct. Mol. Biol., 2010 Apr;17:423-9). This variant is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Dearth LR et al. Carcinogenesis, 2007 Feb;28:289-98). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In addition, this alteration has been determined to be the result of a de novo mutation in an individual meeting Chompret criteria for Li-Fraumini syndrome (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Li-Fraumeni syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 19, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 276 of the TP53 protein (p.Ala276Pro). 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: 428893). 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 affects TP53 function (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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at