Submissions for variant NM_000546.6(TP53):c.814G>T (p.Val272Leu)

dbSNP: rs121912657

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164988	SCV000215682	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-10-18	criteria provided, single submitter	clinical testing	The p.V272L variant (also known as c.814G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 814. The valine at codon 272 is replaced by leucine, an amino acid with highly similar properties. This alteration was first described in a proband with childhood-onset acute lymphoblastic leukemia (ALL) whose personal and family history satisfied diagnostic criteria for classic Li-Fraumeni syndrome (Felix CA J. Clin. Invest. 1992 Feb;89(2):640-7). Functional studies from multiple groups show deficient transactivation capacity and greatly reduced DNA binding activity compared to wild type (Malcikova J Biol. Chem. 391(2-3):197-205. Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9. IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9). This amino acid position is highly conserved through primates, but not in lower available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV001221969	SCV001394046	likely pathogenic	Li-Fraumeni syndrome	2022-02-20	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 12358). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 1737852; Invitae). 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 272 of the TP53 protein (p.Val272Leu).
Genetics and Molecular Pathology, SA Pathology	RCV000013152	SCV002761563	likely pathogenic	Li-Fraumeni syndrome 1	2020-08-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000013152	SCV004931523	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-20	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 20128691, 29979965]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 1737852].
OMIM	RCV000013152	SCV000033399	pathogenic	Li-Fraumeni syndrome 1	1992-08-01	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432989	SCV000509976	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443570	SCV000509977	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426429	SCV000509978	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437100	SCV000509979	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443589	SCV000509980	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427077	SCV000509981	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437706	SCV000509982	likely pathogenic	Medulloblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420507	SCV000509983	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431193	SCV000509984	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434905	SCV000509985	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417682	SCV000509986	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428361	SCV000509987	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439021	SCV000509988	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only