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)

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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.

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)

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.