ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.919+1G>A (rs1131691039)

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Total submissions: 3
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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 2020-10-09 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 and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals with Li-Fraumeni syndrome (PMID: 29070607, 29324801, 20805372). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 633606). 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). For these reasons, this variant has been classified as Pathogenic.
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

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