Submissions for variant NM_000546.6(TP53):c.344A>G (p.His115Arg)

dbSNP: rs730881996

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000696891	SCV001737943	likely benign	Li-Fraumeni syndrome	2025-01-16	reviewed by expert panel	curation	NM_000546.6(TP53):c.344A>G variant in TP53 is a missense variant predicted to cause substitution of Histidine by Arginine at amino acid 115 (p.His115Arg). This variant has an allele frequency of 0.000003101 (5/1612276 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). 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 = 0.0464; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BS3, BP4. (Bayesian Points: -4; VCEP specifications version 2.2; 1/16/2025).
GeneDx	RCV000161021	SCV000211740	likely benign	not provided	2020-09-22	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16687402, 27527004, 11313981, 31395738, 29979965)
Ambry Genetics	RCV000575197	SCV000676296	likely benign	Hereditary cancer-predisposing syndrome	2022-10-24	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	RCV000696891	SCV000825472	uncertain significance	Li-Fraumeni syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 115 of the TP53 protein (p.His115Arg). 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: 182925). 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	RCV000575197	SCV001345638	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 115 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). Functional studies have shown the mutant protein to exhibit normal transactivation activity in a yeast transactivation assay (PMID 12826609 and IARC database) and to be functional in human cell growth assays (PMID: 29979965, 30224644). The mutant protein has shown a partially reduced binding affinity for the p53 response element from the p21 promoter (PMID: 16687402). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192619	SCV001360869	uncertain significance	not specified	2019-01-30	criteria provided, single submitter	clinical testing	Variant summary: The variant, TP53 c.344A>G (p.His115Arg) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245988 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.344A>G in individuals affected with Li-Fraumeni Syndrome or related tumor phenotypes has been reported. Publications reported experimental evidence evaluating an impact on protein function, where one study demonstrated that the variant, p.H115R, does not affect the transactivation activity on eight different promoter elements (including p21) (data taken from the IARC Database, reference: Kato 2003), while another study demonstrated that the variant protein has a decreased oligonucleotide binding activity in an EMSA assay (where the probe contained the p53 response element from the p21 promoter) (Zupnick 2006). These data does not allow unequivocal conclusions about the variant effect. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000696891	SCV005425742	uncertain significance	Li-Fraumeni syndrome	2024-04-17	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 115 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). Functional studies have shown the mutant protein to exhibit normal transactivation activity in a yeast transactivation assay (PMID 12826609 and IARC database) and to be functional in human cell growth assays (PMID: 29979965, 30224644). The mutant protein has shown a partially reduced binding affinity for the p53 response element from the p21 promoter (PMID: 16687402). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.