ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.919+1G>A

dbSNP: rs1131691039
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000991150 SCV001142564 likely pathogenic Li-Fraumeni syndrome 2019-08-28 reviewed by expert panel curation The c.919+1G>A is canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is a proband with a de novo observation with bilateral, metachronous breast cancer without mention of parental confirmation (PM6_Supporting; PMID: 28509937). In summary, TP53 c.919+1G>A meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PVS1_Strong, PM2_Supporting, PM6_Supporting.
Invitae RCV000991150 SCV001382474 pathogenic Li-Fraumeni syndrome 2024-01-29 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 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 Li-Fraumeni syndrome (PMID: 20805372, 29070607, 29324801). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 633606). 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.
Ambry Genetics RCV003307417 SCV003998799 pathogenic Hereditary cancer-predisposing syndrome 2023-05-11 criteria provided, single submitter clinical testing The c.919+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 7 of the TP53 gene. This alteration has been reported in families meeting classic Li Fraumeni syndrome criteria and/or Chompret criteria for LFS (Marcel V et al. J Med Genet, 2009 Nov;46:766-72; Wilson JR et al. J Med Genet, 2010 Nov;47:771-4; Wong ESY et al. NPJ Genom Med, 2016 Jan;1:15003; Aceto GM et al. Breast Cancer Res Treat, 2019 Jun;175:479-485; Haque MM et al. Sci Rep, 2018 Aug;8:11705; Stoltze U et al. PLoS One, 2018 Jan;13:e0190050). This alteration has also been reported as a de novo observation with bilateral, metachronous breast cancer without mention of parental confirmation (O'Shea R et al. Fam Cancer, 2018 Jan;17:123-128). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV003992389 SCV004809802 pathogenic Adrenocortical carcinoma, hereditary 2024-04-04 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000782136 SCV004933174 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.
Academic Center for Education, Culture and Research, Motamed Cancer Institute RCV000782136 SCV000914200 pathogenic Li-Fraumeni syndrome 1 2019-05-21 no assertion criteria provided clinical testing
MutSpliceDB: a database of splice sites variants effects on splicing, NIH RCV001578272 SCV001805840 not provided not provided no assertion provided in vivo

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