Submissions for variant NM_000546.6(TP53):c.517G>T (p.Val173Leu)

dbSNP: rs876660754

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000694763	SCV000823221	pathogenic	Li-Fraumeni syndrome	2023-07-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val173 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 21343334; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 9407971, 12826609, 16474844, 20407015, 23967324). 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. ClinVar contains an entry for this variant (Variation ID: 376668). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 173 of the TP53 protein (p.Val173Leu).
Genetic Services Laboratory, University of Chicago	RCV001821147	SCV002065920	likely pathogenic	not provided	2022-01-14	criteria provided, single submitter	clinical testing	DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.517G>T, in exon 5 that results in an amino acid change, p.Val173Leu. The p.Val173Leu change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Val173Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has not previously been described in individuals with Li-Fraumeni syndrome, however, the p.Val173Leu amino acid change occurs in a region of the TP53 gene where other missense sequence changes (p.Val173Met, Val173Ala) have been described in individuals with TP53-related disorders (PMID: 21343334, 29070607). Experimental studies have demonstrated that this sequence change impacts the function of the TP53 protein (PMID: 20407015, 16474844, 12826609, 9407971, 23967324) and this residue is located in a well-established functional domain (PMID: 29099487). Based on this evidence, this sequence change is classified as likely pathogenic.
Genome-Nilou Lab	RCV002289542	SCV002582387	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289541	SCV002583049	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002289542	SCV002644142	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-12	criteria provided, single submitter	clinical testing	The p.V173L pathogenic mutation (also known as c.517G>T), located in coding exon 4 of the TP53 gene, results from a G to T substitution at nucleotide position 517. The valine at codon 173 is replaced by leucine, an amino acid with highly similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Another alteration at the same codon, p.V173M (c.517G>A), has been detected in a family meeting clinical criteria for Li-Fraumeni Syndrome (Achatz M et al. Cancer Lett. 2007 Jan; 245(1-2):96-102). 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 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.
Myriad Genetics, Inc.	RCV002289541	SCV004932383	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8631304, 10229196, 23246812].
Database of Curated Mutations (DoCM)	RCV000428483	SCV000509861	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438383	SCV000509862	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417683	SCV000509863	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429213	SCV000509864	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439916	SCV000509865	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421780	SCV000509866	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432458	SCV000509867	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440549	SCV000509868	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423312	SCV000509869	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433209	SCV000509870	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443390	SCV000509871	likely pathogenic	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427493	SCV000509872	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434691	SCV000509873	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442009	SCV000509874	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427345	SCV000509875	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785539	SCV000924111	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research