ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.1120G>C (p.Gly374Arg) (rs587781858)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000529612 SCV001142527 likely benign Li-Fraumeni syndrome 2019-08-28 reviewed by expert panel curation This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In summary, TP53 c.1120G>C; p.Gly374Arg meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4 and BS3.
Ambry Genetics RCV000217404 SCV000273745 likely benign Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
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.
Invitae RCV000529612 SCV000629775 uncertain significance Li-Fraumeni syndrome 2020-08-22 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 374 of the TP53 protein (p.Gly374Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with breast cancer (PMID: 31321604). ClinVar contains an entry for this variant (Variation ID: 230269). This variant has been reported not to substantially affect TP53 protein 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 Health, Inc RCV000217404 SCV001345853 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-10 criteria provided, single submitter clinical testing

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