Submissions for variant NM_000546.6(TP53):c.880G>T (p.Glu294Ter)

dbSNP: rs1057520607

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000433836	SCV000516576	pathogenic	not provided	2015-03-31	criteria provided, single submitter	clinical testing	The E294X nonsense variant in the TP53 gene has been reported previously in association with Li-Fraumenisyndrome (Koolipara et al., 2014). It was not 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. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Nonsense variants in nearby residues (E287X, E286X, E298X) have been reported in theHuman Gene Mutation Database in association with TP53-related disorders (Stenson et al., 2014), supportingthe functional importance of this region of the protein. Therefore, we consider E294X as a pathogenic variant.
Ambry Genetics	RCV002374641	SCV002687971	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-31	criteria provided, single submitter	clinical testing	The p.E294* pathogenic mutation (also known as c.880G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 880. This changes the amino acid from a glutamic acid to a stop codon within coding exon 7. This pathogenic mutation has been reported in a patient with bilateral breast cancers diagnosed at age 33 and 41 whose son was reported to have an osteosarcoma diagnosed at age 15 (Veschi S et al. Ann Oncol, 2007 Jun;18 Suppl 6:vi86-92). This mutation was also reported in a pediatric patient with a personal history of choroid plexus carcinoma, Spitzoid melanoma, and myelodysplasia (Kollipara R et al. Pediatr Dev Pathol Nov;17:64-9). 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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV004022313	SCV004930394	pathogenic	Li-Fraumeni syndrome 1	2024-02-21	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
University Health Network, Princess Margaret Cancer Centre	RCV001527467	SCV001738484	pathogenic	Ovarian neoplasm	2021-03-19	no assertion criteria provided	clinical testing