ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.376-2dup (rs751253294)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165040 SCV000215739 likely benign Hereditary cancer-predisposing syndrome 2020-01-31 criteria provided, single submitter clinical testing Other data supporting benign classification;RNA Studies
Invitae RCV000232667 SCV000285192 uncertain significance Li-Fraumeni syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the TP53 gene. It does not directly change the encoded amino acid sequence of the TP53 protein, but it affects a nucleotide within the consensus splice site of the intron. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with a personal and/or family history of breast, ovarian, or endometrial cancer (PMID: 31159747, 28452373, 29522266). ClinVar contains an entry for this variant (Variation ID: 185593). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000235779 SCV000293780 uncertain significance not specified 2016-08-29 criteria provided, single submitter clinical testing This variant is denoted TP53 c.376-2dupA or IVS4-2dupA and consists of a duplication of one nucleotide at the -2 position in intron 4 of the T53 gene. The normal sequence, with the base that is duplicated in braces, is ctac{a}gTAC, where the capital letters are exonic and lowercase are intronic. The adenine (A) nucleotide that is duplicated is conserved across species and is part of the canonical splice acceptor site. Multiple in silico models predict this variant to cause a reduction in use of this natural splice acceptor site, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. TP53 c.376-2dupA was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Based on currently available information, we consider TP53 c.376-2dupA to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985262 SCV000602270 uncertain significance not provided 2019-02-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000165040 SCV000691592 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-09 criteria provided, single submitter clinical testing
GeneKor MSA RCV000165040 SCV000822206 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235779 SCV001370658 uncertain significance not specified 2020-05-07 criteria provided, single submitter clinical testing Variant summary: TP53 c.376-2dupA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3 acceptor site. One predicts the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 249574 control chromosomes (gnomAD). c.376-2dupA has been reported in the literature in one individual affected with endometrial cancer as well as one individual who was referred to test with a hereditary cancer panel (Spurdle_2017, Tsaousis_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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