Submissions for variant NM_000546.6(TP53):c.919+2T>G

dbSNP: rs1131691016

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492618	SCV000581110	pathogenic	Hereditary cancer-predisposing syndrome	2019-08-15	criteria provided, single submitter	clinical testing	The c.919+2T>G intronic pathogenic mutation results from a T to G substitution 2 nucleotides after coding exon 7 in the TP53 gene. This pathogenic mutation has been detected as a de novo finding in an individual with metastatic early onset breast cancer (Ambry internal data). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish this splice donor site, and RNA evidence supports this prediction (Ambry internal data). As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808655	SCV000948769	pathogenic	Li-Fraumeni syndrome	2021-08-28	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 428877). 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. Disruption of this splice site has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 29070607). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 8 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	RCV000492618	SCV002582445	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289666	SCV002583107	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002289666	SCV004932223	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-21	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	RCV001542803	SCV001761179	not provided	not provided		no assertion provided	in vivo