Submissions for variant NM_000546.6(TP53):c.1115A>G (p.Lys372Arg)

dbSNP: rs876658876

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217059	SCV000274681	likely benign	Hereditary cancer-predisposing syndrome	2021-01-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000217059	SCV001346516	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-09	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 372 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies have demonstrated that methylation of Lys372 regulates protein stability and that this variant (p.Lys372Arg) abolishes this effect (PMID 15525938, 17108971), however other studies have shown this variant to be functional in transactivation studies (PMID 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV002288860	SCV002582223	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000217059	SCV002583201	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003401139	SCV004105698	uncertain significance	TP53-related disorder	2023-08-14	criteria provided, single submitter	clinical testing	The TP53 c.1115A>G variant is predicted to result in the amino acid substitution p.Lys372Arg. Methylation studies suggest this variant impacts protein stability (Figures 1E and 4E, Chuikov et al. 2004. PubMed ID: 15525938; Figure 1, Huang et al. 2006. PubMed ID: 17108971). It has also been reported in a mutagenesis study (Table S2 and S3, Giacomelli et al. 2018. PubMed ID: 30224644). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/230970/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.