Submissions for variant NM_000546.6(TP53):c.375+1G>T

dbSNP: rs1567555445

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804919	SCV000944857	pathogenic	Li-Fraumeni syndrome	2022-08-16	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 635393). Disruption of this splice site has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 7887414, 17224268; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 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).
Ambry Genetics	RCV001021045	SCV001182608	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-04-06	criteria provided, single submitter	clinical testing	The c.375+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 3 of the TP53 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however direct evidence is insufficient at this time (Ambry internal data). 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.
GeneDx	RCV000786840	SCV001805078	pathogenic	not provided	2019-10-17	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of a critical region: disrupts the transactivation domain, nuclear export signals, SH3 domain, and DNA binding domain (Zhang 2001, Bode 2004, Pessoa 2014); Published functional studies demonstrate a damaging effect: aberrant splicing (Smardova 2016); Not observed in large population cohorts (Lek 2016); Identified in patients with personal or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx; A different variant affecting the same splice site (c.375G>A) has been reported as pathogenic at GeneDx in association with Li-Fraumeni syndrome and shown to result in a similar splicing impact (Varley 2001, Bougeard 2008, Hettmer 2014, Wasserman 2015); This variant is associated with the following publications: (PMID: 26718964, 28807936)
CeGaT Center for Human Genetics Tuebingen	RCV000786840	SCV002498240	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001021045	SCV002582404	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002290035	SCV002583065	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000786840	SCV000925736	not provided	not provided		no assertion provided	in vitro