Submissions for variant NM_000546.6(TP53):c.1025G>A (p.Arg342Gln)

gnomAD frequency: 0.00001  dbSNP: rs375338359

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000688863	SCV001949925	likely benign	Li-Fraumeni syndrome	2024-09-06	reviewed by expert panel	curation	The NM_000546.6: c.1025G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 342 (p.Arg342Gln). 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). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; SCV000277448.6). Computational predictor scores (BayesDel =-0.2779; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -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_Moderate). This variant has an allele frequency of 0.000006780 (8/1180002 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3, BS2_Supporting, BP4_Moderate, PM2_Supporting. (Bayesian Points: -6; VCEP specifications version 2.0; 9/6/2024)
Ambry Genetics	RCV000213668	SCV000277448	likely benign	Hereditary cancer-predisposing syndrome	2020-12-31	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.
GeneDx	RCV000478259	SCV000565624	likely benign	not provided	2021-03-31	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast and/or ovarian cancer in published literature (Castera 2014); Published functional studies demonstrate no damaging effect: oligomerization, transcription activity, and DNA binding activity similar to wild type (Rollenhagen 1998, Kato 2003, Imagawa 2009); This variant is associated with the following publications: (PMID: 10499619, 28993836, 14559903, 24549055, 9766574, 20978130, 19454241, 24665023, 28861920, 30840781, 25226867, 12826609, 30224644)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688863	SCV000816490	uncertain significance	Li-Fraumeni syndrome	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 342 of the TP53 protein (p.Arg342Gln). This variant is present in population databases (rs375338359, gnomAD 0.01%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 24549055). ClinVar contains an entry for this variant (Variation ID: 233136). 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: 9766574, 12826609). This variant disrupts the p.Arg342 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9766574, 10064694, 16007150, 19454241, 19806023, 20978130, 25226867, 25981898). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV000213668	SCV002052756	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 342 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 functional studies have shown this variant demonstrates DNA binding, tetramerization, transcriptional activation, and growth suppression activities similar to that of wild-type TP53 (PMID: 9766574, 12826609, 19454241, 20978130, 30224644). Another variant at the same amino acid position (p.Arg342Pro) has been shown to be deficient in these activities, indicating the amino acid position may be important for TP53 function. This variant has been reported in an individual affected with breast cancer in the literature (PMID: 24549055). This variant has been identified in 2/250992 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.
Mendelics	RCV002247662	SCV002516104	benign	not specified	2023-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002247662	SCV002570646	likely benign	not specified	2022-07-05	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.1025G>A (p.Arg342Gln) results in a conservative amino acid change located in the p53, tetramerisation domain (IPR010991) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250992 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1025G>A has been reported in the literature as a VUS in settings of multigene panel testing for hereditary breast and ovarian cancer (example, Castera_2014) and as a somatic variant in a variety of tumor settings (COSMIC database, Ten Broeke_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At-least one co-occurrence with another inferred germline pathogenic variant(s) has been reported in an individual with colorectal cancer and a characteristic MSH2-negative/MSH6-negative IHC pattern (Ten Broeke_2018, MSH2 c.1413del, p.Lys471fs), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function (example, Rollenhagen_1998, Kato_2003). These results showed no damaging effect of this variant based on overall transcription activity (TA) on eight different promoters as measured in yeast assays. Multiple clinical diagnostic laboratories and an expert panel (ClinGen TP53 Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 reporting the variant with conflicting assessments (likely benign, n=2; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV000688863	SCV004823725	uncertain significance	Li-Fraumeni syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 342 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 functional studies have shown this variant demonstrates DNA binding, tetramerization, transcriptional activation, and growth suppression activities similar to that of wild-type TP53 (PMID: 9766574, 12826609, 19454241, 20978130, 30224644). Another variant at the same amino acid position (p.Arg342Pro) has been shown to be deficient in these activities, indicating the amino acid position may be important for TP53 function. This variant has been reported in an individual affected with breast cancer in the literature (PMID: 24549055). This variant has been identified in 2/250992 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.