ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.517G>A (p.Val173Met) (rs876660754)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000477355 SCV001142547 pathogenic Li-Fraumeni syndrome 2019-08-28 reviewed by expert panel curation This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). 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 a proband meeting classic Li-Fraumeni syndrome criteria (PS4_Supporting; PMID: 16494995). There is a de novo observation of a proband with a diagnosis of a sarcoma, breast cancer and thyroid cancers under the age of 26 years with parental confirmation (PS2; ClinVar SCV000545293.4). In summary, TP53 p.Val173Met meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3, PM1, PS3, PS4_Supporting, PS2.
Ambry Genetics RCV000214341 SCV000278424 pathogenic Hereditary cancer-predisposing syndrome 2020-09-11 criteria provided, single submitter clinical testing The p.V173M pathogenic mutation (also known as c.517G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 517. The valine at codon 173 is replaced by methionine, an amino acid with highly similar properties. This alteration was detected in a family meeting clinical criteria for Li-Fraumeni Syndrome where the female proband had a soft tissue sarcoma at 23, breast cancer at 43, and a family history of brain and adrenal tumors (Achatz M et al. Cancer Lett. 2007 Jan; 245(1-2):96-102). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in several yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Dearth L et al. Carcinogenesis 2007 Feb;28(2):289-98; Epstein C et al. Oncogene 1998 Apr;16(16):2115-22), although one yeast study showed loss of transactivation but no dominant negative effect (Monti P et al. Mol. Cancer Res. 2011 Mar; 9(3):271-9). Studies conducted in human cell lines indicate this alteration 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). In addition, based on internal structural analysis, this variant is anticipated to result in a 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000223396 SCV000279617 pathogenic not provided 2018-05-25 criteria provided, single submitter clinical testing This variant is denoted TP53 c.517G>A at the cDNA level, p.Val173Met (V173M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant was observed in a family that met clinical diagnostic criteria for Li Fraumeni syndrome (Achatz 2007). Multiple tansactivation and apoptosis activity assays demonstrate loss of TP53 function (Marutani 1999, Baroni 2004, Dearch 2007, Golubovskaya 2008, Monti 2011). TP53 Val173Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. TP53 Val173Met occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the DNA binding domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider TP53 Val173Met to be a pathogenic variant.
Invitae RCV000477355 SCV000545293 pathogenic Li-Fraumeni syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 173 of the TP53 protein (p.Val173Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 30709381, 16494995, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 233951). This variant has been reported to affect TP53 protein function (PMID: 21343334, 12826609). For these reasons, this variant has been classified as Pathogenic.
Database of Curated Mutations (DoCM) RCV000435365 SCV000509876 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418173 SCV000509877 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424469 SCV000509878 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435180 SCV000509879 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418817 SCV000509880 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429546 SCV000509881 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439338 SCV000509882 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418768 SCV000509883 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429913 SCV000509884 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440133 SCV000509885 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423333 SCV000509886 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433605 SCV000509887 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441217 SCV000509888 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423542 SCV000509889 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434638 SCV000509890 likely pathogenic Adrenocortical carcinoma 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785308 SCV000923876 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Institute of Medical Sciences, Banaras Hindu University RCV001255635 SCV001432171 pathogenic Lip and oral cavity carcinoma 2019-04-30 no assertion criteria provided research

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