Submissions for variant NM_000546.6(TP53):c.832C>A (p.Pro278Thr)

dbSNP: rs17849781

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002429348	SCV002680528	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-30	criteria provided, single submitter	clinical testing	The p.P278T pathogenic mutation (also known as c.832C>A), located in coding exon 7 of the TP53 gene, results from a C to A substitution at nucleotide position 832. The proline at codon 278 is replaced by threonine, an amino acid with highly similar properties. This alteration was identified in one family reported to meet LFS criteria (Güran S et al. Cancer Genet. Cytogenet., 2005 Jul;160:164-8). 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 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	RCV002524698	SCV003443708	pathogenic	Li-Fraumeni syndrome	2023-08-11	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). This variant disrupts the p.Pro278 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 8688334, 11370630; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 376643). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 278 of the TP53 protein (p.Pro278Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 15993273).
Myriad Genetics, Inc.	RCV004022234	SCV004931143	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]. This variant is expected to disrupt protein structure [Myriad internal data].
Database of Curated Mutations (DoCM)	RCV000433992	SCV000509060	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442861	SCV000509061	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425201	SCV000509062	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435065	SCV000509063	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442983	SCV000509064	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425878	SCV000509065	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436548	SCV000509066	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418460	SCV000509067	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429149	SCV000509068	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437214	SCV000509069	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419944	SCV000509070	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429755	SCV000509071	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440415	SCV000509072	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Oxford Haemato-Oncology Service, Oxford University Hospitals NHS Foundation Trust	RCV000626445	SCV000734835	drug response	Poly (ADP-Ribose) polymerase inhibitor response	2017-11-27	no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785511	SCV000924083	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research