ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.143A>G (p.Asp48Gly)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV003621963 SCV005627633 likely benign Li-Fraumeni syndrome 2025-01-16 reviewed by expert panel curation The NM_000546.6:c.143A>G variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 48 (p.Asp48Gly). This variant is absent from gnomAD v4.1.0 (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 = -0.086; Align GVGD Class C0) 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 likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3, BP4_Moderate, PM2_Supporting. (Bayesian Points: -5; VCEP specifications version 2.0; 1/16/2025).
Labcorp Genetics (formerly Invitae), Labcorp RCV003621963 SCV004391087 uncertain significance Li-Fraumeni syndrome 2022-12-03 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 48 of the TP53 protein (p.Asp48Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. 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. 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.

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