Submissions for variant NM_000546.6(TP53):c.256G>A (p.Ala86Thr)

dbSNP: rs587782148

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130712	SCV000185599	likely benign	Hereditary cancer-predisposing syndrome	2018-01-29	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	RCV000478688	SCV000571555	uncertain significance	not provided	2021-06-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate functional transactivation and no dominant negative effect over wildtype (Marutani 1999, Kato 2003); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Observed in an individual with malignant mesothelioma (De Rienzo 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12826609, 10519380, 27535533, 15510160, 26554828)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633343	SCV000754565	uncertain significance	Li-Fraumeni syndrome	2024-01-11	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 86 of the TP53 protein (p.Ala86Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with malignant pleural mesothelioma (PMID: 26554828). ClinVar contains an entry for this variant (Variation ID: 141967). 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 with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 10519380, 12826609). 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	RCV000130712	SCV000911118	likely benign	Hereditary cancer-predisposing syndrome	2020-05-20	criteria provided, single submitter	clinical testing
Mendelics	RCV002247510	SCV002516707	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478688	SCV004221350	uncertain significance	not provided	2023-01-31	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/TP53)) and in an individual with mesothelioma (PMID: 26554828 (2016)). Functional analysis has determined that this variant does not impact transactivation capacity and does not display a dominant negative effect (PMIDs: 10519380 (1999), 12826609 (2003)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.