Submissions for variant NM_000546.6(TP53):c.250G>A (p.Ala84Thr)

gnomAD frequency: 0.00001  dbSNP: rs587781307

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000462026	SCV001429622	likely benign	Li-Fraumeni syndrome	2025-01-16	reviewed by expert panel	curation	The NM_000546.6: c.250G>A variant in TP53 is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 84 (p.Ala84Thr). 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 = -0.0501; 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: BP4_Moderate, BS3. (Bayesian Points: -6; VCEP specifications version 2.1; 1/16/2025).
Ambry Genetics	RCV000129026	SCV000172931	likely benign	Hereditary cancer-predisposing syndrome	2020-12-07	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.
Counsyl	RCV000409852	SCV000489003	uncertain significance	Li-Fraumeni syndrome 1	2016-08-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462026	SCV000545271	uncertain significance	Li-Fraumeni syndrome	2024-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 84 of the TP53 protein (p.Ala84Thr). This variant is present in population databases (rs587781307, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 140833). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998253	SCV000888663	likely benign	not specified	2024-10-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129026	SCV000908798	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-29	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 84 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 the mutant protein is functional in a transactivation assay (PMID: 12826609) and in a human cell growth suppression assay (PMID: 30224644). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/250390 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.
Myriad Genetics, Inc.	RCV000409852	SCV004017890	uncertain significance	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV000462026	SCV004823824	uncertain significance	Li-Fraumeni syndrome	2024-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 84 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 the mutant protein is functional in a transactivation assay (PMID: 12826609) and in a human cell growth suppression assay (PMID: 30224644). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/250390 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.