Submissions for variant NM_000546.6(TP53):c.1140del (p.His380fs)

dbSNP: rs1555524108

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537354	SCV000629778	uncertain significance	Li-Fraumeni syndrome	2017-04-03	criteria provided, single submitter	clinical testing	In summary, this variant is a novel frameshift in the final exon of TP53 with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TP53-related disease. This variant disrupts a portion of the C-terminal regulatory domain (residues 363-393) of TP53 that is necessary for full TP53 DNA binding and transactivation activity (PMID: 22178617, 25794615, 26205489). However, this particular variant has not been tested, and the clinical significance of this disruption is unknown. This sequence change deletes 1 nucleotide from exon 11 of the TP53 mRNA (c.1140delT), causing a frameshift at codon 380 (p.His380Glnfs*42). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acids of the TP53 protein, and to extend the protein by an additional 27 amino acids.
Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	RCV003483656	SCV004232434	likely pathogenic	Adrenocortical carcinoma, hereditary; Glioma susceptibility 1; Li-Fraumeni syndrome 1; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Colorectal cancer; Bone marrow failure syndrome 5	2024-01-23	criteria provided, single submitter	clinical testing	The c.1140del variant is not present in 1000 Genomes, EVS, ExAC, gnomAD, Indian Exome Database or our in-house exome database. This variant has not been reported in the literature in individuals affected with TP53-related conditions. It has been previously reported to the ClinVar database (Accession: VCV000458520.6) as ‘Uncertain significance’ by a single submitter. In-silico pathogenicity prediction programs like MutationTaster2, CADD, Varsome, Franklin etc predicted this variant to be likely deleterious, however these predictions were not confirmed by published functional studies. This variant is located at the last exon of the gene that causes frameshift at the 380th amino acid position of the wild-type transcript which disrupts the last 14 amino acids of the TP53 protein and extends the protein by 27 additional amino acid residues, however not predicted to cause nonsense mediated decay of the mRNA. This region is critical to the protein function and several other pathogenic variants in this region have been reported to the clinical databases.