Submissions for variant NM_000546.6(TP53):c.559+1G>T

dbSNP: rs1131691042

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804747	SCV000944670	pathogenic	Li-Fraumeni syndrome	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 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 Li-Fraumeni syndrome-associated tumors (PMID: 23894400, 26911350; Invitae). ClinVar contains an entry for this variant (Variation ID: 649747). 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.
Color Diagnostics, LLC DBA Color Health	RCV001183083	SCV001348738	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-01-15	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the canonical +1 position of intron 5 splice donor site of the TP53 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional studies have not been reported for this variant, this variant is expected to result in an absent or non-functional TP53 protein. This variant has been reported in individuals affected with sarcoma (PMID: 23894400) and early-onset breast cancer (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Genome-Nilou Lab	RCV001183083	SCV002582377	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002290446	SCV002583038	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002290446	SCV004931260	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-14	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002290446	SCV005368406	pathogenic	Li-Fraumeni syndrome 1	2024-08-21	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS1_MOD,PS4_SUP,PM2_SUP
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV001580378	SCV001810067	not provided	not provided		no assertion provided	in vivo