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

dbSNP: rs1131691003

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492543	SCV000581081	pathogenic	Hereditary cancer-predisposing syndrome	2016-12-02	criteria provided, single submitter	clinical testing	The c.96+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 2 of the TP53 gene. This alteration has been identified in multiple individuals meeting Chompret criteria (Ambry internal data). 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 experimental 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 a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002523444	SCV003317138	pathogenic	Li-Fraumeni syndrome	2025-01-15	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 27157322, 32658383, 32817165; internal data). ClinVar contains an entry for this variant (Variation ID: 428859). 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.
Myriad Genetics, Inc.	RCV003485592	SCV004932733	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.
deCODE genetics, Amgen	RCV003485592	SCV004022270	likely pathogenic	Li-Fraumeni syndrome 1	2023-07-21	no assertion criteria provided	research	The variant NM_000238.4:c.3060del (chr17:7676381) in TP53 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.