ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.994-1G>A

dbSNP: rs587782272
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Myriad Genetics, Inc. RCV002288645 SCV004931182 likely pathogenic Li-Fraumeni syndrome 1 2024-02-21 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.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre RCV003992194 SCV004809791 pathogenic Adrenocortical carcinoma, hereditary 2024-04-04 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002288645 SCV002583100 pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000131124 SCV002582438 pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
GeneDx RCV000786811 SCV001816973 pathogenic not provided 2019-12-13 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (Hwang 2003); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31105275, 30720243, 25045116, 25525159, 12610779, 24240112, 23374397)
Labcorp Genetics (formerly Invitae), Labcorp RCV001380070 SCV001578012 pathogenic Li-Fraumeni syndrome 2023-12-22 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 9 of the TP53 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Li Fraumeni syndrome (PMID: 10980596, 12610779, 20522432, 26014290, 26911350). ClinVar contains an entry for this variant (Variation ID: 142161). Studies have shown that disruption of this splice site results in the inclusion of a portion of intron 9 and introduces a premature termination codon (PMID: 10980596). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131124 SCV000186055 pathogenic Hereditary cancer-predisposing syndrome 2018-10-25 criteria provided, single submitter clinical testing The c.994-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 9 of the TP53 gene This aleration was reported in an individual with classic Li-Fraumeni syndrome (Hwang SJ et al. Am J Hum Genet. 2003 Apr;72(4):975-83). In addition to the clinical data presented in the literature, 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 a disease-causing mutation.
Dr. Peter K. Rogan Lab, Western University RCV005886927 SCV006897647 not provided Ovarian serous cystadenocarcinoma no classification provided in vitro
Dr. Peter K. Rogan Lab, Western University RCV005886927 SCV006897646 not provided Ovarian serous cystadenocarcinoma no classification provided in vitro
Dr. Peter K. Rogan Lab, Western University RCV005886926 SCV006897644 not provided Colon adenocarcinoma no classification provided in vitro
Dr. Peter K. Rogan Lab, Western University RCV005886925 SCV006897643 not provided Familial cancer of breast no classification provided in vitro
MutSpliceDB: a database of splice sites variants effects on splicing, NIH RCV000786811 SCV000925703 not provided not provided no classification provided in vitro

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