Submissions for variant NM_000546.6(TP53):c.833C>T (p.Pro278Leu)

dbSNP: rs876659802

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214784	SCV000276644	pathogenic	Hereditary cancer-predisposing syndrome	2019-08-27	criteria provided, single submitter	clinical testing	The p.P278L pathogenic mutation (also known as c.833C>T), located in coding exon 7 of the TP53 gene, results from a C to T substitution at nucleotide position 833. The proline at codon 278 is replaced by leucine, an amino acid with similar properties. This alteration was identified as a de novo alteration in a female patient with multiple primary tumors, including liposarcoma at 41, bilateral Paget's disease and breast cancer at 42 and 45, and two malignant histiocytomas at 48 and 49 (Speiser P, Br. J. Cancer. 1996 Jul; 74(2):269-73). Functional characterization has shown that this alteration has a loss of transactivation capacity, dominant negative characteristics, and a defect in DNA binding (Monti P et al. Mol. Cancer Res. 2011 Mar; 9(3):271-9; Malcikova et al. J Biol. Chem. 391(2-3):197-205; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Dearth LR et al. Carcinogenesis. 2007 Feb; 28(2):289-98). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Malecka KA et al.Oncogene. 2009 Jan; 28(3):325-33). In addition, other alterations at this same amino acid position have been associated with Li-Fraumeni syndrome (Güran S et al. Cancer Genet. Cytogenet. 2005 Jul; 160(2):164-8; Bougeard G et al. J. Med. Genet. 2001 Apr; 38(4):253-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001042706	SCV001206406	pathogenic	Li-Fraumeni syndrome	2024-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 278 of the TP53 protein (p.Pro278Leu). 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: 8688334, 19556618, 21761402, 32817165). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 232497). Invitae Evidence Modeling incorporating data from in vitro 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, 16861262, 20128691, 21343334, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001541668	SCV001759693	pathogenic	not provided	2022-07-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation, dominant negative effect, and loss of growth suppression ability (Kato et al., 2003; Dearth et al., 2007; Malcikova et al., 2010; Monti et al., 2011; Giacomelli et al., 2018; Kotler et al., 2018); 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; This variant is associated with the following publications: (PMID: 9572492, 29979965, 21343334, 14559903, 21761402, 17646286, 20128691, 16861262, 17606709, 2263646, 10914716, 10949938, 11590071, 30720243, 30840781, 34663841, 33804295, 15510160, 12826609, 30224644, 8688334, 32817165, 31105275)
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785311	SCV000923879	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Institute of Medical Sciences, Banaras Hindu University	RCV001374441	SCV001571404	pathogenic	Gallbladder cancer	2020-10-30	no assertion criteria provided	research