Submissions for variant NM_000546.6(TP53):c.827C>A (p.Ala276Asp)

dbSNP: rs786202082

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223364	SCV000276875	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-22	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000236401	SCV000293907	likely pathogenic	not provided	2016-02-05	criteria provided, single submitter	clinical testing	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.
Genome-Nilou Lab	RCV000223364	SCV002582350	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288879	SCV002583011	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515676	SCV002969084	uncertain significance	Li-Fraumeni syndrome	2024-01-04	criteria provided, single submitter	clinical testing	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.
Myriad Genetics, Inc.	RCV002288879	SCV004931405	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-20	criteria provided, single submitter	clinical testing	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].