ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.376-2A>G (rs786202799)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165794 SCV000216540 likely pathogenic Hereditary cancer-predisposing syndrome 2015-09-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000480344 SCV000568762 likely pathogenic not provided 2018-08-24 criteria provided, single submitter clinical testing This variant is denoted TP53 c.376-2A>G or IVS4-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 4 of the TP53 gene. This variant destroys a canonical splice site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. However, Chappuis et al. (1999) and Athanasakis et al. (2014) both found via cDNA analysis that this variant results in an in-frame loss of seven amino acids in the DNA binding domain (Bode 2004). Functional assays performed on tumor cells harboring this variant found reduced or absent transactivation of typical TP53 targets (Chappuis 1999, Athanasakis 2014, Agnoletto 2015). TP53 c.376-2A>G was observed in a kindred reported to have features of Li-Fraumeni syndrome (Wu 2011) and was also identified in an individual with colorectal cancer (Siraj 2017) and in tumor and adjacent normal tissue from a woman with ovarian cancer and basal cell carcinoma (Kupryjanczyk 1993). Based on the currently available information, we consider TP53 c.376-2A>G to be a likely pathogenic variant.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785343 SCV000923911 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000554039 SCV000629814 likely pathogenic Li-Fraumeni syndrome 2017-10-24 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 and likely results in an absent or disrupted protein product. This variant has been reported in individuals affected with B-cell chronic lymphocytic leukemia and in a family affected with Li-Fraumeni Syndrome (PMID: 25587027, 25544776, 21305319). In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID:  20522432). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.
MutSpliceDB: a database of splice sites variants effects on splicing,NIH RCV000480344 SCV000925731 not provided not provided no assertion provided in vitro

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