Submissions for variant NM_000546.6(TP53):c.646G>T (p.Val216Leu)

dbSNP: rs730882025

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001042741	SCV001206442	uncertain significance	Li-Fraumeni syndrome	2023-04-28	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 376670). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). 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. 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 216 of the TP53 protein (p.Val216Leu).
Ambry Genetics	RCV002365461	SCV002656919	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-29	criteria provided, single submitter	clinical testing	The p.V216L pathogenic mutation (also known as c.646G>T), located in coding exon 5 of the TP53 gene, results from a G to T substitution at nucleotide position 646. The valine at codon 216 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.V216M (c.646G>A), has been detected in a child diagnosed with adrenocorticol carcinoma and in an individual with a personal history of alveolar rhabdomyosarcoma and soft tissue sarcoma (Bougeard G et al. J. Clin. Oncol. 2015 Jul;33:2345-52; Zerdoumi Y et al. Hum Mol Genet, 2017 07;26:2812). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321589	SCV004026689	likely pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004022246	SCV004930554	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-15	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Database of Curated Mutations (DoCM)	RCV000442710	SCV000509917	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426649	SCV000509918	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437749	SCV000509919	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420083	SCV000509920	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431215	SCV000509921	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437980	SCV000509922	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417716	SCV000509923	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427972	SCV000509924	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439081	SCV000509925	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422099	SCV000509926	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428855	SCV000509927	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785309	SCV000923877	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research