Submissions for variant NM_000546.6(TP53):c.1123C>T (p.Gln375Ter)

dbSNP: rs1555524156

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563669	SCV000664405	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-21	criteria provided, single submitter	clinical testing	The p.Q375* variant (also known as c.1123C>T), located in coding exon 10 of the TP53 gene, results from a C to T substitution at nucleotide position 1123. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This alteration occurs at the 3' terminus of theTP53 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 19 amino acids of the protein. The exact functional effect of this alteration is unknown. This variant was detected in a patient with choroid plexus carcinoma (Penkert J et al. J Hematol Oncol, 2022 Aug;15:107). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no dominant negative effect (Giacomelli AO et al. Nat Genet, 2018 Oct;50:1381-1387). Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702325	SCV000831175	uncertain significance	Li-Fraumeni syndrome	2024-04-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln375*) in the TP53 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the TP53 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 35974385). ClinVar contains an entry for this variant (Variation ID: 480739). This variant disrupts a region of the TP53 protein in which other variant(s) (p.Arg379Leu) have been observed in individuals with TP53-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV002289787	SCV002582001	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000563669	SCV002583198	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing