ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.814G>A (p.Val272Met) (rs121912657)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV001527085 SCV001737924 pathogenic Li-Fraumeni syndrome 1 2021-04-20 reviewed by expert panel curation This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in 4 probands meeting Chompret criteria (PS4_Moderate; PMID: 25584008, 23175693, IARC, NIH). There are de novo observations in 2 probands with childhood rhabdomyosarcoma, osteosarcoma, without parental confirmation (PM6_Strong; PMID: IARC, NIH). In summary, TP53 c.814G>A (p.Val272Met) meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PS3, PS4_Moderate, PM6_Strong.
Ambry Genetics RCV000165304 SCV000216025 pathogenic Hereditary cancer-predisposing syndrome 2020-09-23 criteria provided, single submitter clinical testing The p.V272M pathogenic mutation (also known as c.814G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 814. The valine at codon 272 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in a French family with features suggestive of Li-Fraumeni syndrome, a patient diagnosed with rhabdomyosarcoma at age 1 and osteosarcoma at age 2, as well as a patient diagnosed with medulloblastoma at age 3 (Bougeard G et al. J. Med. Genet. 2008 Aug;45(8):535-8; Renaux-Petel M et al. J. Med. Genet. 2017 Oct 25). This alteration was also identified in a patient with late onset adrenal cortical carcinoma (Raymond VM et al. J. Clin. Endocrinol. Metab. 2013 Jan; 98(1):E119-25). The p.V272M alteration has been reported as a somatic alteration in a variety of tumors (Marinelli M et al. Haematologica 2013 Mar; 98(3):371-5; Chiaretti S et al. Genes Chromosomes Cancer 2011 Apr; 50(4):263-74; Chang MT et al. Cancer Discov. 2018 02;8:174-183). This alteration is a well-known temperature sensitive alteration that causes abnormal protein folding and prevents DNA binding at temperatures above 37 degrees Celsius (da Costa NM et al. Cell Cycle 2012 Dec;11(24):4570-8). Functional studies have demonstrated that this alteration interferes with p53 up-regulation in response to DNA damaging agents and shows loss of transactivation capacity in yeast based assays (Barnas Cet al. Int. J. Cancer 1997 Mar;71(1):79-87). 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 not well 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.
Invitae RCV000457645 SCV000545259 uncertain significance Li-Fraumeni syndrome 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 272 of the TP53 protein (p.Val272Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs121912657, ExAC 0.01%). This variant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 18511570, 23175693, 25584008). ClinVar contains an entry for this variant (Variation ID: 185814). This variant has been reported to affect TP53 protein function (PMID: 9290701, 9635828, 12826609, 16861262, 22710932). 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) RCV000434295 SCV000509950 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441086 SCV000509951 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424351 SCV000509952 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434621 SCV000509953 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443071 SCV000509954 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424542 SCV000509955 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432177 SCV000509956 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443052 SCV000509957 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425268 SCV000509958 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436402 SCV000509959 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418746 SCV000509960 likely pathogenic Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426406 SCV000509961 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436602 SCV000509962 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785341 SCV000923909 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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