Submissions for variant NM_000546.6(TP53):c.794T>C (p.Leu265Pro)

dbSNP: rs879253942

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235981	SCV000292887	pathogenic	not provided	2015-05-12	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted TP53 c.794T>C at the cDNA level, p.Leu265Pro (L265P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). This variant was observed in at least two families with classic Li-Fraumeni syndrome (Cornelis 1997, Ruijs 2010). Several yeast based functional assays have demonstrated that this mutation severely impacts p53 function and stability (Brachmann 1996, Dearth 2007, Monti 2007, Monti 2011). In addition, this mutation conferred reduced DNA binding activity and expression of downstream target genes in an in vitro functional assay (Malcikova 2010). This variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Leu265Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Leu265Pro occurs at a position that is conserved across species and is located in the DNA binding domain and region of interaction with HIPK1, ZNF385A, AXIN1 and E4F1 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554509	SCV000629871	pathogenic	Li-Fraumeni syndrome	2023-08-01	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 265 of the TP53 protein (p.Leu265Pro). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 17606709, 20128691, 21343334). 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. ClinVar contains an entry for this variant (Variation ID: 245777). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 9067756, 20522432). It has also been observed to segregate with disease in related individuals.
Ambry Genetics	RCV000564617	SCV000672371	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-08	criteria provided, single submitter	clinical testing	The p.L265P pathogenic mutation (also known as c.794T>C), located in coding exon 7 of the TP53 gene, results from a T to C substitution at nucleotide position 794. The leucine at codon 265 is replaced by proline, an amino acid with similar properties. This alteration has been reported in multiple individuals in families meeting both classic Li-Fraumeni syndrome (LFS) criteria and Chompret criteria (Cornelis RS et al, Hum. Mutat. 1997; 9(2):157-63; Ruijs MW et al. J. Med. Genet. 2010 Jun;47(6):421-8; IARC TP53 database). In a study of TP53 genotype-phenotype associations, this variant was classified as a severe deficiency allele based on in vitro luciferase assays (Monti P et al, Mol Cancer Res 2011. 9:271-279). The authors observed that severe deficiency alleles are associated with more severe clinical features than alleles classified as partial deficiency. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity, dominant negative effect and predicted to affect several p53 isoforms in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). 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.
Counsyl	RCV000662855	SCV000785730	likely pathogenic	Li-Fraumeni syndrome 1	2017-11-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000564617	SCV002582356	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000662855	SCV002583017	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662855	SCV004017893	likely pathogenic	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9067756, 20522432]. This variant is expected to disrupt protein structure [Myriad internal data].
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257518	SCV001434344	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation