Submissions for variant NM_000546.6(TP53):c.832C>G (p.Pro278Ala)

dbSNP: rs17849781

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567850	SCV000665233	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-01-22	criteria provided, single submitter	clinical testing	The p.P278A variant (also known as c.832C>G), located in coding exon 7 of the TP53 gene, results from a C to G substitution at nucleotide position 832. The proline at codon 278 is replaced by alanine, an amino acid with highly similar properties. This alteration has been identified in a patient meeting Chompret criteira (personal communication). This alteration has also been reported in a 1 of 109 women diagnosed with breast cancer who underwent genetic testing for suspected germline TP53 mutations (Melhem-Bertrandt A et al. Cancer. 2012 Feb;118:908-13). This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in functional studies in yeast and human cell lines (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Jordan JJ et al. Mol. Cancer Res., 2010 May;8:701-16; Wang B et al. Cell Death Differ., 2014 Apr;21:521-32). Additional studies showed this variant to be deficient in DNA binding, apoptosis induction, and growth suppression (Wang B et al. Cell Death Differ. 2014 Apr;21:521-32; Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8). Other alterations at this same amino acid position (p.P278S, p.P278T) have previously been reported in the germline of individuals diagnosed with Li-Fraumeni syndrome (Bougeard G et al. J. Med. Genet. 2001 Apr; 38(4):253-7; Güran S et al. Cancer Genet. Cytogenet. 2005 Jul; 160(2):164-8; Speiser P et al. Br. J. Cancer. 1996 Jul; 74(2):269-73). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in DNA binding (Petty TJ et al. EMBO J. 2011 Jun;30:2167-76; Ambry internal data). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688854	SCV000816480	uncertain significance	Li-Fraumeni syndrome	2024-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 278 of the TP53 protein (p.Pro278Ala). 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: 21761402, 25428789, 25896519, 27328919, 32817165; Invitae). ClinVar contains an entry for this variant (Variation ID: 376645). 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: 12826609, 20407015, 24076587, 29979965, 30224644). 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.
GeneDx	RCV001584114	SCV001819055	pathogenic	not provided	2020-01-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression activity (Kato 2003, Kotler 2018) and very weak transactivation in a system in which TP53 activity is increased (Jordan 2010); Observed in individuals with TP53-related cancers referred for genetic testing at GeneDx and in published literature (Melhem-Bertrandt 2012, Churpek 2015, and Mirabello 2015); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29979965, 30720243, 20407015, 25896519, 25428789, 21761402, 30840781)
Myriad Genetics, Inc.	RCV004022235	SCV004932974	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: 24076587, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Fulgent Genetics, Fulgent Genetics	RCV005018718	SCV005651979	likely pathogenic	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Familial pancreatic carcinoma; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5	2024-02-05	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785477	SCV000924049	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research