ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.523C>T (p.Arg175Cys)

gnomAD frequency: 0.00001  dbSNP: rs138729528
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Total submissions: 31
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000704159 SCV001429624 uncertain significance Li-Fraumeni syndrome 2022-06-27 reviewed by expert panel curation This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). This variant is within a codon that is an established hotspot in the TP53 gene (PM1). This variant has been reported in 2 probands meeting Revised Chompret criteria (PS4_Supporting; PMID: 31119730, internal laboratory contributor(SCV000903055.2)). Transactivation assays show partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). This variant has been observed in 5 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor, SCV000833097.4). In summary, the clinical significance of TP53 c.523C>T (p.Arg175Cys) is uncertain for Li-Fraumeni Syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: PP3_Moderate; PM1; PS4_Supporting; BS3_Supporting; BS2_Supporting.
GeneDx RCV000235329 SCV000293015 uncertain significance not provided 2023-10-30 criteria provided, single submitter clinical testing Observed in individuals with a personal history of breast or ovarian cancer (PMID: 22006311, 30216591, 28724667, 31119730, 35820297); Published functional studies demonstrate no damaging effect: retained apoptosis and growth suppression activities, partially functional transactivation per IARC, and intact transactivation of typical p53 targets (PMID: 30224644, 29979965, 12826609, 8062826, 9546439, 9632751, 11375890); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22006311, 26619011, 23792586, 29979965, 30216591, 25927356, 30720243, 31016814, 30352134, 31119730, 30089713, 21343334, 12826609, 8825920, 8164043, 30224644, 8062826, 11375890, 9546439, 9632751, 28861920, 28724667, 11370630, 30840781, 21761402, 26556035, 27323394, 30741375, 30979843, 33257846, 33245408, 35820297, 34863587, 15510160)
Ambry Genetics RCV000574439 SCV000664387 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-03 criteria provided, single submitter clinical testing The p.R175C variant (also known as c.523C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 523. The arginine at codon 175 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was identified in one patient with ovarian cancer at 64 years of age, with a family history of early onset breast cancer, colon cancer, and leukemia (Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7). This alteration is located in the DNA binding domain and has shown a partial decrease in transactivation capacity for some, but not all downstream targets in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. U.S.A. 2003 Jul;100:8424-9). However, studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Additional functional studies in mammalian cells have also shown this variant to behave similarly to wild type in terms of protein conformation, transactivation, growth suppression, apoptotic activities, and protein level regulation (Ory K et al. EMBO J. 1994 Aug;13:3496-504; Ryan K et al. Mol. Cell. Biol. 1998 Jul;18:3692-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000704159 SCV000833097 uncertain significance Li-Fraumeni syndrome 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 175 of the TP53 protein (p.Arg175Cys). This variant is present in population databases (rs138729528, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 22006311, 25503501, 28724667, 31119730). ClinVar contains an entry for this variant (Variation ID: 245851). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644, 33245408). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002268012 SCV002551069 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
3billion RCV003152698 SCV003842091 likely pathogenic Li-Fraumeni syndrome 1 2023-02-23 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TP53 -related disorder (PMID: 22006311). However, the evidence of pathogenicity is insufficient at this time. Different missense changes at the same codon (p.Arg175Gly, p.Arg175His, p.Arg175Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012374, VCV000182963, VCV000376649). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002268012 SCV004223718 uncertain significance not specified 2023-11-13 criteria provided, single submitter clinical testing Variant summary: TP53 c.523C>T (p.Arg175Cys) results in a non-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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251284 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.523C>T has been reported in the literature in individuals affected with breast, ovarian and other cancers ((example, Walsh_2011, Sun_2017, Weber-Lassalle_2018, Sheng_2020)) but to our knowledge, it has not been reported in individuals affected with Li-Fraumeni Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least two publication reports experimental evidence evaluating an impact on protein function. These results showed similar levels of cell cyle arrest and apoptotic functions to wild type (e.g. Ryan_1998), and partially functional transcriptional activity as measured in a yeast-based assay (Kato_2003). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as uncertain significance.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV003483596 SCV004228252 uncertain significance Hereditary breast ovarian cancer syndrome 2023-10-12 criteria provided, single submitter curation PM1, PP3_mod, PS4_sup, BS2sup, BS3sup, See ClinVar ClinGen TP53 Variant Curation Expert Panel classification (Class 3). According to the ACMG gene specific: TP53 criteria we chose these criteria: PS4 (supporting pathogenic): This variant has been reported in 2 probands meeting Revised Chompret criteria (PS4_Supporting; PMID: 31119730, internal laboratory contributor(SCV000903055.2, PM1 (medium pathogenic): This variant is within a codon that is an established hotspot in the TP53 gene (PM1), PP3 (medium pathogenic): BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65, BS2 (supporting benign): This variant has been observed in 5 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor, SCV000833097.4). , BS3 (supporting benign): Transactivation assays show partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting)
Database of Curated Mutations (DoCM) RCV000439625 SCV000509158 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421969 SCV000509159 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433090 SCV000509160 likely pathogenic Uterine carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439855 SCV000509161 likely pathogenic Ovarian serous cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423061 SCV000509162 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433333 SCV000509163 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444463 SCV000509164 likely pathogenic Nasopharyngeal neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426785 SCV000509165 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434308 SCV000509166 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442812 SCV000509167 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427794 SCV000509168 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438017 SCV000509169 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417778 SCV000509170 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424499 SCV000509171 likely pathogenic Prostate adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435664 SCV000509172 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418017 SCV000509173 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429015 SCV000509174 likely pathogenic Gallbladder carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439251 SCV000509175 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418929 SCV000509176 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429222 SCV000509177 likely pathogenic B-cell chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440307 SCV000509178 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422641 SCV000509179 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785238 SCV000923806 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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