Submissions for variant NM_000546.6(TP53):c.341T>C (p.Leu114Ser)

gnomAD frequency: 0.00001  dbSNP: rs781724995

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537102	SCV000629804	uncertain significance	Li-Fraumeni syndrome	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 114 of the TP53 protein (p.Leu114Ser). This variant is present in population databases (rs781724995, gnomAD 0.0009%). 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: 458536). 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, 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.
Color Diagnostics, LLC DBA Color Health	RCV001177908	SCV001342212	uncertain significance	Hereditary cancer-predisposing syndrome	2018-12-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821513	SCV002066966	uncertain significance	not specified	2021-10-11	criteria provided, single submitter	clinical testing	DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.341T>C, in exon 4 that results in an amino acid change, p.Leu114Ser. This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0. 0004 % (dbSNP rs781724995). The p.Leu114Ser change affects a moderately conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Leu114Ser substitution. This sequence change does not appear to have been previously described in individuals with TP53-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Leu114Ser change remains unknown at this time.
Genome-Nilou Lab	RCV001177908	SCV002582109	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289729	SCV002582672	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001177908	SCV002612855	likely benign	Hereditary cancer-predisposing syndrome	2022-05-18	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.