Submissions for variant NM_000546.6(TP53):c.464C>G (p.Thr155Ser)

gnomAD frequency: 0.00002  dbSNP: rs786202752

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165724	SCV000216465	likely benign	Hereditary cancer-predisposing syndrome	2019-03-22	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804037	SCV000943929	uncertain significance	Li-Fraumeni syndrome	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 155 of the TP53 protein (p.Thr155Ser). This variant is present in population databases (rs786202752, 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: 186179). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000986051	SCV001134870	likely benign	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192618	SCV001360867	uncertain significance	not specified	2024-06-24	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.464C>G (p.Thr155Ser) results in a conservative amino acid change located in the p53 DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251290 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.464C>G has been reported in the literature in Malignant Peripheral Nerve Sheath tumors (MPNSTs) (Verdijk_2010 citing Mawrin_2002) and as a germline likely benign variant among individuals in gnomAD (Andrade_2019). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Co-occurrences with another pathogenic variant has been reported (PALB2 c.79G>T, p.27X; internal sample), providing supporting evidence for a benign role. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Carlsson_2009). The IARC database reports this as a functional variant based on overall transcriptional activity (TA) on 8 different promoters as measured in yeast assays by Kato et al. The following publications have been ascertained in the context of this evaluation (PMID: 30352134, 19558493, 20010306). ClinVar contains an entry for this variant (Variation ID: 186179). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000165724	SCV002530459	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000804037	SCV004829283	uncertain significance	Li-Fraumeni syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 155 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). Experimental studies have shown that this variant did not impact function in yeast transactivation assays (PMID: 12826609), human cell proliferation assays (PMID: 29979965), and human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with primary head and neck squamous cell carcinoma (PMID: 21159183). This variant has been identified in 1/31370 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.