Submissions for variant NM_000546.6(TP53):c.376-1G>T

dbSNP: rs868137297

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001882697	SCV002242785	pathogenic	Li-Fraumeni syndrome	2021-11-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1210292). Disruption of this splice site has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 24382691, 27501770, 29752822, 32930885; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the TP53 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432).
Ambry Genetics	RCV003375345	SCV004093339	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-14	criteria provided, single submitter	clinical testing	The c.376-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 4 of the TP53 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, and the impacted region is critical for protein function (Ambry internal data). Another alteration impacting the same acceptor site (c.376-1G>A) has been detected in individuals with a history of early-onset rhabdomyosarcoma (Hettmer S et al. Cancer. 2014 Apr; 120(7):1068-75; Villani A et al. Lancet Oncol. 2016 Sep;17:1295-305), and RNA studies have demonstrated that the c.376-1G>A alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV001580379	SCV001810068	not provided	not provided		no assertion provided	in vivo
Clinical Genetics and Genomics, Karolinska University Hospital	RCV004797631	SCV005419176	likely pathogenic	TP53-related disorder	2024-10-01	no assertion criteria provided	clinical testing