Submissions for variant NM_000546.6(TP53):c.994-1G>C

dbSNP: rs587782272

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221716	SCV000276846	pathogenic	Hereditary cancer-predisposing syndrome	2015-07-07	criteria provided, single submitter	clinical testing	The c.994-1G>C intronic pathogenic mutation, results from a G to C substitution one nucleotide upstream from coding exon 9 of the TP53 gene. This alteration has been previously described in an individual with breast cancer diagnosed at age 28y and 36y as well as melanoma diagnosed in her 30s (Verselis SJ, et al. Oncogene 2000 Aug; 19(37):4230-5). Examination of RNA from this patient showed a transcript derived from the use of a cryptic acceptor site causing the insertion of 44 bp of intron 9 into the coding sequence, and an alternate termination signal at codon 359. Functional analysis of this alteration in a yeast based assay showed reduced transactivation capacity compared to wild type (Verselis SJ, et al. Oncogene 2000 Aug; 19(37):4230-5). Two other alterations involving the c.994-1 position (c.994-1G>A and c.994-1G>T) have been identified in individuals with tumors in the Li Fraumeni syndrome spectrum (Hwang SJ, et al. Am J Hum Genet. 2003 Apr;72(4):975-83; Ruijis MW, et al. J Med Genet. 2010 Jun;47(6):421-8). In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice acceptor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804263	SCV000944163	pathogenic	Li-Fraumeni syndrome	2024-03-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 9 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: 20522432, 26014290). ClinVar contains an entry for this variant (Variation ID: 232659). 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	RCV000221716	SCV002582437	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288878	SCV002583098	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288878	SCV004932966	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	RCV000786812	SCV000925704	not provided	not provided		no assertion provided	in vitro