Submissions for variant NM_000546.6(TP53):c.832C>T (p.Pro278Ser)

dbSNP: rs17849781

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522600	SCV000617072	pathogenic	not provided	2023-01-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced or abolished transactivation and apoptotic activity; results in a dominant-negative effect (Epstein et al., 1998; Flaman et al., 1998; Bougeard et al., 2001; Campomenosi et al., 2001; de Vries et al., 2002; Kato et al., 2003; Dearth et al., 2007; Monti et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with history consistent with Li-Fraumeni syndrome (Bougeard et al., 2001); This variant is associated with the following publications: (PMID: 26655088, 9364015, 23264849, 26425688, 25431194, 29979965, 30840781, 11867759, 12826609, 16861262, 9572492, 11429705, 8633021, 9524109, 9546439, 21343334, 15993273, 21763698, 21949389, 17606709, 15161705, 9635858, 15280671, 25579085, 31081129, 30720243, 15510160, 30224644, 11370630)
Ambry Genetics	RCV000562528	SCV000664791	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-16	criteria provided, single submitter	clinical testing	The p.P278S pathogenic mutation (also known as c.832C>T), located in coding exon 7 of the TP53 gene, results from a C to T substitution at nucleotide position 832. The proline at codon 278 is replaced by serine, an amino acid with similar properties. This variant has been identified in individuals meeting Chompret criteria for Li Fraumeni syndrome (Bougeard G et al. J. Med. Genet., 2001 Apr;38:253-7; Evans DG et al. J Med Genet, 2022 02;59:115-121). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and dominant negative effect in yeast and mammalian based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Epstein CB et al. Oncogene, 1998 Apr;16:2115-22; Campomenosi P et al. Oncogene, 2001 Jun;20:3573-9; Dearth LR et al. Carcinogenesis, 2007 Feb;28:289-98; Monti P et al. Mol. Cancer Res., 2011 Mar;9:271-9). 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 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). Internal structural analysis indicate that this variant may destabilize the structure in the DNA binding domain (Kitayner M et al. Mol. Cell, 2006 Jun;22:741-53; Ambry internal data). 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.
Invitae	RCV000633344	SCV000754566	likely pathogenic	Li-Fraumeni syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 278 of the TP53 protein (p.Pro278Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 11370630, 15993273, 16258005, 33758026). ClinVar contains an entry for this variant (Variation ID: 376642). 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: 8633021, 11370630, 12826609, 21343334, 23264849, 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000633344	SCV004847698	likely pathogenic	Li-Fraumeni syndrome	2019-04-02	criteria provided, single submitter	clinical testing	The p.Pro278Ser variant in TP53 has been reported in 2 individuals with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome (Bougeard 2001, Guran 2005, Monti 2007). It was absent from large population studies. In vitro functional studies provide some evidence that this variant impacts protein function by disrupting its transactivation activity (Brachmann 1996, Epstein 1998, Bougeard 2001, Kato 2003, Dearth 2007, Monti 2011). It has also been reported as a common somatic mutation across multiple tumor types (COSMIC Database, https://cancer.sanger.ac.uk/cosmic/). Computational prediction tools and conservation analysis are consistent with pathogenicity. 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 dominan Li-Fraumeni syndrome. ACMG/AMP criteria applied: PM2, PS3_Moderate, PP3, PS4_Supporting.
Myriad Genetics, Inc.	RCV004022233	SCV004930435	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-20	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 11867759]. This variant is expected to disrupt protein structure [Myriad internal data].
Database of Curated Mutations (DoCM)	RCV000432977	SCV000509034	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439725	SCV000509035	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421997	SCV000509036	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432228	SCV000509037	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444293	SCV000509038	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426679	SCV000509039	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433428	SCV000509040	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443572	SCV000509041	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427714	SCV000509042	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437941	SCV000509043	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442821	SCV000509044	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427094	SCV000509045	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435645	SCV000509046	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785527	SCV000924099	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research