17-7673793-G-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000546.6(TP53):c.827C>A(p.Ala276Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A276P) 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.827C>A | p.Ala276Asp | missense_variant | 8/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.827C>A | p.Ala276Asp | missense_variant | 8/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461838Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727220
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 20, 2024 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 12509279]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 22, 2023 | The p.A276D pathogenic mutation (also known as c.827C>A), located in coding exon 7 of the TP53 gene, results from a C to A substitution at nucleotide position 827. The alanine at codon 276 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been reported in an individual with a personal history of multiple malignancies including breast cancer, melanoma and synchronous non-small cell lung cancers (Penkert J et al. J Hematol Oncol, 2022 Aug;15:107). 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 has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). Another alteration at the same codon, p.A276G (c.827C>G), 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 amino acid position is highly conserved in available vertebrate species. In addition, the p.A276D 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2016 | This variant is denoted TP53 c.827C>A at the cDNA level, p.Ala276Asp (A276D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCC>GAC). This variant was shown to display near absent transactivation capacity in yeast based luciferase reporter assays and was unable to suppress growth in a colony growth assay (Ko 2002, Kato 2003). TP53 Ala276Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Ala276Asp occurs at a position that is conserved across species and is located in DNA binding domain and within the region of interaction with HIPK1, ZNF385A, AXIN1, and E4F1 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider TP53 Ala276Asp to be a likely pathogenic variant. - |
Li-Fraumeni syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 276 of the TP53 protein (p.Ala276Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TP53-related conditions (PMID: 35974385). ClinVar contains an entry for this variant (Variation ID: 232683). 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: 12509279, 12826609, 26497680, 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at