Submissions for variant NM_000546.6(TP53):c.517G>A (p.Val173Met)

dbSNP: rs876660754

Total submissions: 23

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	2023-09-26	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 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 variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 173 of the TP53 protein (p.Val173Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 16494995, 30709381; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 233951). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 21343334, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000477355	SCV004847712	likely pathogenic	Li-Fraumeni syndrome	2019-04-02	criteria provided, single submitter	clinical testing	The p.Val173Met variant in TP53 has been reported in 2 individuals with TP53-related cancers (Achatz 2007, Gallardo-Alvarado 2019). It was absent from large population studies. This variant has also been reported in ClinVar, and has been seen as a de novo variant in a patient with TP53-related tumors by another clinical diagnostic lab (Variation ID: 233951). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Monti 2011, Bouaoun 2016); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LFS. ACMG/AMP Criteria applied: PM2, PM6, PS3_Moderate, PP3, PS4_Supporting.
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	Gastric adenocarcinoma	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	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, 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
BRCAlab, Lund University	RCV000214341	SCV002589027	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-26	no assertion criteria provided	clinical testing