Submissions for variant NM_000546.6(TP53):c.1120G>C (p.Gly374Arg)

gnomAD frequency: 0.00003  dbSNP: rs587781858

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000529612	SCV001142527	benign	Li-Fraumeni syndrome	2024-08-05	reviewed by expert panel	curation	The NM_000546.6:c.1120G>C variant in TP53 is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 374 (p.Gly374Arg). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2, Internal lab contributors: SCV000273745.6). 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 (PMIDs: 12826609, 29979965, 30224644) (BS3). Computational predictor scores (BayesDel = -0.0546; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -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_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BP4_moderate. (Bayesian Points: -10; VCEP specifications version 2.0; 7/24/2024)
Ambry Genetics	RCV000217404	SCV000273745	likely benign	Hereditary cancer-predisposing syndrome	2018-07-30	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.
GeneDx	RCV000235558	SCV000293250	uncertain significance	not provided	2017-09-06	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.1120G>C at the cDNA level, p.Gly374Arg (G374R) at the protein level, and results in the change of a Glycine to an Arginine (GGT>CGT). This variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Gly374Arg was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Gly374Arg occurs at a position that is not conserved and is located in the C-terminal regulatory domain and a nuclear localization signal (Shaulsky 1990, Bode 2004, Pessoa 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether TP53 Gly374Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529612	SCV000629775	uncertain significance	Li-Fraumeni syndrome	2024-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 374 of the TP53 protein (p.Gly374Arg). This variant is present in population databases (rs587781858, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 31321604). ClinVar contains an entry for this variant (Variation ID: 230269). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 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.
Color Diagnostics, LLC DBA Color Health	RCV000217404	SCV001345853	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 374 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant does not impact TP53 protein function (PMID: 12826609, 30224644). This variant has been reported in an individual affected with sporadic breast cancer (PMID: 31321604). This variant has been identified in 2/282716 chromosomes 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.
All of Us Research Program, National Institutes of Health	RCV000529612	SCV004823717	uncertain significance	Li-Fraumeni syndrome	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 374 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have shown that this variant behaved as wild-type in yeast transcriptional transactivation studies and human cell growth suppression assays (PMID: 12826609, 30224644). This variant has been reported in an individual affected with sporadic breast cancer (PMID: 31321604). This variant has been identified in 2/282716 chromosomes 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV005230108	SCV005872465	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003929915	SCV004745908	likely benign	TP53-related disorder	2023-08-07	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).