ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.578A>G (p.His193Arg)

dbSNP: rs786201838
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Total submissions: 30
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164329 SCV000214960 pathogenic Hereditary cancer-predisposing syndrome 2021-08-13 criteria provided, single submitter clinical testing The p.H193R pathogenic mutation (also known as c.578A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 578. The histidine at codon 193 is replaced by arginine, an amino acid with highly similar properties. This variant has previously been reported in an individual from a family meeting classic Li Fraumeni syndrome criteria, in an individual meeting Chompret criteria, and in several unrelated individuals with early onset Li-Fraumeni spectrum tumors (Frebourg T et al. Am. J. Hum. Genet. 1995 Mar; 56(3):608-15; Nandikolla AG et al. Breast Cancer (Dove Med Press), 2017 Mar;9:207-215; Fortes FP et al. Braz. J. Med. Biol. Res. 2015 Jul;48:610-5; Bouaoun L et al. IARC TP53 database [version R18, April 2016]. Hum. Mutat. 2016 Sep;37:865-76). This alteration has also been reported in multiple breast cancer cohorts (Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Li JY et al. Int J Cancer, 2019 01;144:281-289; Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays, a dominant negative effect, and reduced DNA binding activity (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000255425 SCV000322118 pathogenic not provided 2023-01-11 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: defective DNA binding, transactivation, and growth suppression ability (Kato et al., 2003; Malcikova et al., 2010; Monti et al., 2011; Kotler et al., 2018); 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: 17606709, 9627118, 15280671, 7887414, 19367569, 20128691, 21343334, 26425688, 9546439, 16322298, 16861262, 11238194, 21190917, 1458490, 30816478, 25945745, 29752822, 28724667, 30720243, 30840781, 31105275, 32817165, 15161705, 22265402, 30076369, 15510160, 29979965, 12826609, 28356770)
Invitae RCV000460847 SCV000545345 pathogenic Li-Fraumeni syndrome 2023-07-28 criteria provided, single submitter clinical testing Experimental studies have shown that this missense change affects TP53 function (PMID: 9627118, 12826609, 16861262, 20128691, 21343334). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 193 of the TP53 protein (p.His193Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome-associated tumors (PMID: 7887414, 22265402, 25945745, 28724667; Invitae). ClinVar contains an entry for this variant (Variation ID: 184979). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. For these reasons, this variant has been classified as Pathogenic.
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo RCV000429618 SCV001450485 pathogenic Squamous cell carcinoma of the head and neck criteria provided, single submitter case-control
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255425 SCV001469323 likely pathogenic not provided 2020-09-01 criteria provided, single submitter clinical testing The variant has been reported in individuals with Li-Fraumeni syndrome related cancers in the published literature (PMID: 29752822 (2018), 28724667 (2017), 25945745 (2015), 22265402 (2012), 17606709 (2007), 7887414 (1995)). Functional data indicates that this variant acts in a dominant negative manner and disrupts the transcriptional transactivation and DNA binding activity of the TP53 protein (PMID: 21343334 (2011), 20128691 (2010), 16861262 (2007), 12826609 (2003), 9627118 (1998)). Based on the available information, we predict that the variant is likely pathogenic.
Genome-Nilou Lab RCV000164329 SCV002582375 likely pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002288732 SCV002583036 likely pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
Baylor Genetics RCV003474857 SCV004204277 pathogenic Adrenocortical carcinoma, hereditary 2022-08-09 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV002288732 SCV004930956 likely pathogenic Li-Fraumeni syndrome 1 2024-02-15 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15221755, 20128691, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7887414, 28356770].
Database of Curated Mutations (DoCM) RCV000418086 SCV000508466 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428340 SCV000508467 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439433 SCV000508468 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418288 SCV000508469 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429618 SCV000508470 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439827 SCV000508471 likely pathogenic Papillary renal cell carcinoma, sporadic 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423052 SCV000508472 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433342 SCV000508473 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440903 SCV000508474 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423280 SCV000508475 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434391 SCV000508476 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445148 SCV000508477 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427767 SCV000508478 likely pathogenic Prostate adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434549 SCV000508479 likely pathogenic Ovarian serous cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445029 SCV000508480 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424475 SCV000508481 likely pathogenic Uterine carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435651 SCV000508482 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417979 SCV000508483 likely pathogenic B-cell chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425611 SCV000508484 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435870 SCV000508485 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785346 SCV000923914 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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