ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.535C>A (p.His179Asn) (rs587780070)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564826 SCV000665284 likely pathogenic Hereditary cancer-predisposing syndrome 2016-12-30 criteria provided, single submitter clinical testing The p.H179N variant (also known as c.535C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 535. The histidine at codon 179 is replaced by asparagine, an amino acid with similar properties. This alteration has been reported as a somatic mutation 25 times in various tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). This variant is reported to have greatly decreased transactivation capacity as well as a dominant negative activity in yeast based functional studies (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Dearth LR et al. Carcinogenesis, 2007 Feb;28:289-98; Brachmann RK et al. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4091-5). An additional functional study showed that this alteration has exonuclease activity similar to wildtype but has significantly reduced DNA binding activity (Ahn J et al. Cell Cycle. 2009 May 15;8(10):1603-15). <span style="background-color:initial">This variant is in the DNA binding domain and is one of four amino acid residues required for zinc binding and protein stabilization<span style="background-color:initial"> (Martin et al <span style="background-color:initial">Hum. Mutat. 2002 Feb;19(2):149-64). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al., Science 1994 Jul; 265(5170):346-55). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000695193 SCV000823676 uncertain significance Li-Fraumeni syndrome 2019-01-28 criteria provided, single submitter clinical testing This sequence change replaces histidine with asparagine at codon 179 of the TP53 protein (p.His179Asn). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 376609). Experimental studies in yeast and cell lines have shown that this variant can disrupt the transcriptional transactivation activity and protein function of the TP53 protein (PMID: 9290701, 8633021, 16861262, 12826609, 10616528, 19462533). 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.
Database of Curated Mutations (DoCM) RCV000422109 SCV000508409 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433706 SCV000508410 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440898 SCV000508411 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422797 SCV000508412 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433494 SCV000508413 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445154 SCV000508414 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427824 SCV000508415 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434154 SCV000508416 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444321 SCV000508417 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424599 SCV000508418 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434865 SCV000508419 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418067 SCV000508420 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424807 SCV000508421 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435925 SCV000508422 likely pathogenic Carcinoma of gallbladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419091 SCV000508423 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429415 SCV000508424 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440508 SCV000508425 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419301 SCV000508426 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430449 SCV000508427 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only

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