ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.537T>G (p.His179Gln)

dbSNP: rs876660821
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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000815181 SCV000955628 pathogenic Li-Fraumeni syndrome 2023-09-03 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 179 of the TP53 protein (p.His179Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer or acute myeloid leukemia (PMID: 19556618, 26230955, 28724667). ClinVar contains an entry for this variant (Variation ID: 376607). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). This variant disrupts the p.His179 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19556618). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf RCV001293868 SCV001482286 pathogenic Hereditary cancer-predisposing syndrome criteria provided, single submitter research
GeneDx RCV002264935 SCV002547072 likely pathogenic not provided 2022-10-14 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity, and a dominant-negative effect (Unger et al., 2003; Waddell et al., 2001; Kotler et al., 2018; Kato et al., 2003; Giacomelli 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; Identified in a child with rhabdomyosarcoma as well as an individual with breast cancer (Wagener et al., 2021; Sun et al., 2017); This variant is associated with the following publications: (PMID: 34972722, 30337059, 32923889, 30840781, 30720243, 22540896, 19759556, 28724667, 15510160, 10802655, 8336941, 8355677, 15848166, 16474844, 29979965, 30224644, 12826609, 11593407, 33840814, 11435891, 26619011)
Genome-Nilou Lab RCV001293868 SCV002582382 likely pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002289527 SCV002583042 likely pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV001293868 SCV002643411 pathogenic Hereditary cancer-predisposing syndrome 2015-06-25 criteria provided, single submitter clinical testing The p.H179Q pathogenic mutation (also known as c.537T>G), located in coding exon 4 of the TP53 gene, results from a T to G substitution at nucleotide position 537. The histidine at codon 179 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a French family with a clinical history suggestive of Li-Fraumeni syndrome (LFS) (Bougeard G et al. J Med Genet. 2008 Aug;45(8):535-8), and a woman with breast cancer at 27 years of age (Sheng S et al. Int. J. Cancer, 2020 01;146:487-495). A similar nucleotide alteration, c.537T>A, which results in the same p.H179Q amino acid alteration was detected in a child diagnosed with two classic LFS cancers and was confirmed to be a de novo mutation (Gonzalez KD et al. J Med Genet. 2009 Oct;46(10):689-93). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient 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). 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 available evidence, p.H179Q is classified as a pathogenic mutation.
Database of Curated Mutations (DoCM) RCV000444951 SCV000508371 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421558 SCV000508372 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431364 SCV000508373 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444976 SCV000508374 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425896 SCV000508375 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436580 SCV000508376 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444017 SCV000508377 likely pathogenic Uterine carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425641 SCV000508378 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437195 SCV000508379 likely pathogenic Ovarian serous cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419975 SCV000508380 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429821 SCV000508381 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436952 SCV000508382 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420594 SCV000508383 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431267 SCV000508384 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441082 SCV000508385 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423857 SCV000508386 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428479 SCV000508387 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439103 SCV000508388 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421045 SCV000508389 likely pathogenic Gallbladder carcinoma 2016-05-31 no assertion criteria provided literature only

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