Submissions for variant NM_000546.6(TP53):c.892G>T (p.Glu298Ter)

dbSNP: rs201744589

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000559898	SCV001142557	pathogenic	Li-Fraumeni syndrome	2024-08-05	reviewed by expert panel	curation	The NM_000546.6 c.892G>T (p.Glu298Ter) is a TP53 nonsense variant inducing a premature termination codon upstream of p.Lys351. The variant is predicted to undergo nonsense-mediated decay (PVS1). This variant has been observed in 1 family meeting Revised Chompret criteria. This proband was under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors: SCV000278127.7). At least one individual with this variant was found to have a variant allele fraction 25-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, SCV000278127.7). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1, PS4_Supporting, PP4, PM2_Supporting. (Bayesian Points: 11; VCEP specifications version 2.0; 7/24/2024)
Eurofins Ntd Llc (ga)	RCV000079204	SCV000111074	pathogenic	not provided	2012-09-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000216964	SCV000278127	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-22	criteria provided, single submitter	clinical testing	The p.E298* pathogenic mutation (also known as c.892G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 892. This changes the amino acid from a glutamic acid to a stop codon within coding exon 7. This alteration was detected in a large Li-Fraumeni kindred consisting of 33 carriers of the alteration and a total of 32 tumors (Wu CC et al. Hum. Genet. 2011 Jun; 129(6):663-73). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000559898	SCV000629883	pathogenic	Li-Fraumeni syndrome	2024-07-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu298*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 12610779, 21305319). ClinVar contains an entry for this variant (Variation ID: 93323). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV004019532	SCV004933100	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.
GeneDx	RCV000079204	SCV005396380	pathogenic	not provided	2024-05-08	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34589931, 25525159, 37029683, 30720243, 33300245, 34780712, 37519790, 35328131, 21305319, 31105275, 29077256, 34805717, 12610779, 33372952)
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785528	SCV000924100	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257516	SCV001434342	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation