Submissions for variant NM_000546.6(TP53):c.875A>G (p.Lys292Arg)

gnomAD frequency: 0.00001  dbSNP: rs121912663

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000457955	SCV001949911	likely benign	Li-Fraumeni syndrome	2025-01-16	reviewed by expert panel	curation	The NM_000546.6: c.875A>G variant in TP53 is a missense variant predicted to cause substitution of lysine by arginine at amino acid 292 (p.Lys292Arg). This variant has an allele frequency of 6.196e-7 (1/1614016 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.00998; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BS3, BP4. (Bayesian Points: -4; VCEP specifications version 2.2; 1/16/2025)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457955	SCV000545302	uncertain significance	Li-Fraumeni syndrome	2023-04-07	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 406577). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 292 of the TP53 protein (p.Lys292Arg).
Ambry Genetics	RCV000573281	SCV000664424	uncertain significance	Hereditary cancer-predisposing syndrome	2016-08-29	criteria provided, single submitter	clinical testing	The p.K292R variant (also known as c.875A>G), located in coding exon 7 of the TP53 gene, results from an A to G substitution at nucleotide position 875. The lysine at codon 292 is replaced by arginine, an amino acid with highly similar properties. This alteration is located in the functionally critical DNA binding domain, and has been shown to have transactivation capacity similar to wild type in yeast-based functional studies (IARC TP53 database: Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0004% (greater than 250000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000573281	SCV000910134	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-31	criteria provided, single submitter	clinical testing