ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.375+2T>C (rs1555526469)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586625 SCV000697441 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-10-14 criteria provided, single submitter clinical testing Variant summary: The TP53 c.375+2T>C variant involves the alteration of a highly conserved intronic nucleotide at the consensus splice-site at intron 4. 4/5 splice prediction tools predict that this variant eliminates the 5' splicing donor site. This variant is absent in 120402 control chromosomes from ExAC. This variant has been reported as a germline variant in one 20-year-old patient with a metaplastic carcinoma and an invasive ductal carcinoma. The patient also carried BRCA1 exon 3 deletion (Bell_2014). Both variants can be pathogenic and explain the early onset age of this patient. The variant of interest was also found in multiple tumor samples (colorectal carcinoma, esophageal adenocarcinoma and head and neck squamous cell carcinoma), including two confirmed somatic occurrences (Georgieva_2008, Soubeyran_2011, Agrawal_2012 and Seiwert_2015). Taken together, this variant is currently classified as likely pathogenic.
Invitae RCV000692558 SCV000820386 likely pathogenic Li-Fraumeni syndrome 2018-03-15 criteria provided, single submitter clinical testing This sequence change affects a donor 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 is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with early onset breast cancer who had a concomitant pathogenic BRCA1 variant (PMID: 24916180). ClinVar contains an entry for this variant (Variation ID: 439316). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
MutSpliceDB: a database of splice sites variants effects on splicing,NIH RCV000505908 SCV000925734 not provided not provided no assertion provided in vitro
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505908 SCV000602268 likely pathogenic not provided 2017-02-23 criteria provided, single submitter clinical testing

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