Submissions for variant NM_000546.6(TP53):c.370T>A (p.Cys124Ser)

gnomAD frequency: 0.00001  dbSNP: rs730881997

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV001048454	SCV001737944	likely benign	Li-Fraumeni syndrome	2025-02-06	reviewed by expert panel	curation	The NM_000546.6: c.370T>A variant in TP53 is a missense variant predicted to cause substitution of Cysteine by Serine at amino acid 124 (p.Cys124Ser). This variant received a total of 0.5 points across 1 proband. (PS4 not met; Internal lab contributors). 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 = 0.258 ; Align GVGD = Class C65 are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3, PP3_Moderate (Bayesian Points: -2; VCEP specifications version 2.2; 2/6/2025).
GeneDx	RCV000161022	SCV000211741	uncertain significance	not provided	2015-11-20	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.370T>A at the cDNA level, p.Cys124Ser (C124S) at the protein level, and results in the change of a Cysteine to a Serine (TGC>AGC). This variant has been studied functionally, but with varied results regarding its effect on p53 function (Buzek 2002, Baroni 2004, Stoner 2009, Kim 2010). This variant has also been reported as having functional transactivation activity in the International Agency for Research on Cancer (IARC) TP53 database based on functional assays by Kato et al (2003). TP53 Cys124Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Cys124Ser occurs at a position that is conserved in mammals and is located in the DNA binding domain and in a region known to interact with multiple proteins (Uniprot). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether TP53 Cys124Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000574455	SCV000672382	likely benign	Hereditary cancer-predisposing syndrome	2021-09-27	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	RCV000574455	SCV000908795	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001048454	SCV001212461	uncertain significance	Li-Fraumeni syndrome	2024-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 124 of the TP53 protein (p.Cys124Ser). This variant is present in population databases (rs730881997, gnomAD 0.01%). 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: 182926). 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, 25584637, 29979965, 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.