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	2016-10-07	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 not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6500 samples (13000 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0004% (greater than 250000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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
Invitae	RCV001203248	SCV001374404	pathogenic	Li-Fraumeni syndrome	2023-08-10	criteria provided, single submitter	clinical testing	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). Disruption of this splice site has been observed in individuals with clinical features of TP53-related conditions (PMID: 27157322, 32658383; Invitae). ClinVar contains an entry for this variant (Variation ID: 482212). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
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