Submissions for variant NM_000546.6(TP53):c.353C>T (p.Thr118Ile)

gnomAD frequency: 0.00001  dbSNP: rs1064794141

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV001724024	SCV001949915	uncertain significance	Li-Fraumeni syndrome 1	2021-08-03	reviewed by expert panel	curation	This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). This variant has been observed in 2 60+ year old females without a cancer diagnosis (BS2_Supporting; Ambry Genetics). 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, the clinical significance of TP53 c.353C>T (p.Thr118Ile) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3_Moderate, BS2_Supporting, BS3
GeneDx	RCV000484765	SCV000567956	uncertain significance	not provided	2022-11-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: functional transactivation and no impact on growth suppression activity (Kato et al., 2003; Kotler et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19336573, 22187033, 15510160, 30886117, 12826609, 30224644, 29979965)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526166	SCV000629806	uncertain significance	Li-Fraumeni syndrome	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 118 of the TP53 protein (p.Thr118Ile). 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. ClinVar contains an entry for this variant (Variation ID: 419837). 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). 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.
Ambry Genetics	RCV000569220	SCV000664386	likely benign	Hereditary cancer-predisposing syndrome	2022-12-02	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.
Color Diagnostics, LLC DBA Color Health	RCV000569220	SCV001356471	uncertain significance	Hereditary cancer-predisposing syndrome	2018-11-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484765	SCV005625957	uncertain significance	not provided	2024-12-05	criteria provided, single submitter	clinical testing	The TP53 c.353C>T (p.Thr118Ile) variant has been reported in the published literature in functional studies suggesting that the variant is not damaging to protein function (PMIDs: 29979965 (2018), 30224644 (2018), 12826609 (2003)). The frequency of this variant in the general population, 0.0000066 (1/152210 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.