Submissions for variant NM_000546.6(TP53):c.580C>T (p.Leu194Phe)

dbSNP: rs587780071

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115728	SCV000149637	likely pathogenic	not provided	2019-06-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with respect to transcriptional activation, apoptosis, and growth suppression activities (Epstein 1998, Kato 2003, Marzec 2015, Kotler 2018); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with bilateral breast or lung cancer (Melhem-Bertrandt 2012, Villani 2016); This variant is associated with the following publications: (PMID: 26181206, 18223694, 17070499, 26942128, 25733866, 26378048, 27381050, 26425688, 28580174, 27956623, 26009011, 16443602, 19429664, 12667443, 17344317, 12779080, 7935394, 10884390, 9572492, 28397142, 12826609, 29979965, 21761402, 27501770, 30720243, 30840781)
Invitae	RCV001377420	SCV001574751	likely pathogenic	Li-Fraumeni syndrome	2022-05-27	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects TP53 function (PMID: 9572492, 12826609, 18818522, 29979965, 30224644). 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. 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: 127817). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 21761402, 27501770; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 194 of the TP53 protein (p.Leu194Phe).
Genome-Nilou Lab	RCV002288599	SCV002582374	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288598	SCV002583035	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002288599	SCV002648064	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-11	criteria provided, single submitter	clinical testing	The p.L194F pathogenic mutation (also known as c.580C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 580. The leucine at codon 194 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been reported in a female diagnosed with bilateral invasive breast cancer (Melhem-Bertrandt A et al. Cancer. 2012 Feb;118:908-13). 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). 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 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.
Myriad Genetics, Inc.	RCV002288598	SCV004933219	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)	RCV000419908	SCV000508858	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426684	SCV000508859	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436065	SCV000508860	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418414	SCV000508861	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429595	SCV000508862	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439843	SCV000508863	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417813	SCV000508864	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428029	SCV000508865	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439186	SCV000508866	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421548	SCV000508867	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434383	SCV000508868	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University	RCV003997297	SCV004046824	likely pathogenic	Adrenal cortex carcinoma		no assertion criteria provided	clinical testing