Submissions for variant NM_000546.6(TP53):c.96+1G>T

dbSNP: rs1131691003

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566426	SCV000667182	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-11	criteria provided, single submitter	clinical testing	The c.96+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 2 of the TP53 gene. This variant was reported in an individual with features consistent with Li-Fraumeni syndrome (Pondrom M et al. Pediatr Blood Cancer, 2020 Sep;67:e28486). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this 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). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763420	SCV000894157	pathogenic	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Carcinoma of colon; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001203248	SCV001374404	pathogenic	Li-Fraumeni syndrome	2023-08-10	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: 482212). Disruption of this splice site has been observed in individuals with clinical features of TP53-related conditions (PMID: 27157322, 32658383; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 3 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).
Genome-Nilou Lab	RCV000566426	SCV002582414	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289813	SCV002583075	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002289813	SCV004931081	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-12	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV003320444	SCV004024562	not provided	not provided		no assertion provided	research