Submissions for variant NM_000546.6(TP53):c.376-2A>G

dbSNP: rs786202799

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165794	SCV000216540	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-05-29	criteria provided, single submitter	clinical testing	The c.376-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 4 in the TP53 gene. This alteration was identified once in a series of LFS families; however, clinical details were not provided (Wu CC et al. Hum. Genet., 2011 Jun;129:663-73). In addition, this alteration has been identified in individuals diagnosed with colorectal cancer, breast cancer, and B-CLL (Athanasakis E et al. Oncotarget, 2014 Dec;5:12635-45; Siraj AK et al. Hum. Genet., 2017 11;136:1431-1444; Li JY et al. Int. J. Cancer, 2019 01;144:281-289). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000480344	SCV000568762	pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing and demonstrated to result in an in-frame loss of seven amino acids (Chappuis 1999, Athanasakis 2014); Functional assays performed on tumor cells harboring this variant found reduced or absent transactivation of typical TP53 targets (Chappuis 1999, Athanasakis 2014, Agnoletto 2015); Observed in a kindred reported to have features of Li-Fraumeni syndrome and also identified in individuals with breast, colorectal, or ovarian cancer (Kupryjanczyk 1993, Wu 2011, Siraj 2017, Li 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 21305319, 27189670, 10567903, 11595686, 24729566, 26857262, 25544776, 28497333, 8506342, 28975465, 15510160, 33790576, 29751042, 30720243, 29752822, 29070607, 25587027, 10864200)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554039	SCV000629814	pathogenic	Li-Fraumeni syndrome	2024-09-27	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 21305319, 25544776, 25587027, 29752822; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 186236). 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	RCV000165794	SCV002582398	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288750	SCV002583060	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288750	SCV004931067	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-13	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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785343	SCV000923911	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000480344	SCV000925731	not provided	not provided		no assertion provided	in vitro
Institute of Medical Sciences, Banaras Hindu University	RCV001374443	SCV001571406	likely pathogenic	Gallbladder cancer	2020-10-30	no assertion criteria provided	research