ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.372C>A (p.Cys124Ter)

dbSNP: rs1555526478
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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 RCV000541004 SCV001142558 pathogenic Li-Fraumeni syndrome 2024-08-05 reviewed by expert panel curation The NM_000546.6 c.372C>A (p.Cys124Ter) is a TP53 nonsense variant upstream of p.Lys351. The variant is predicted to undergo nonsense-mediated decay (PVS1; PMID: 22233476). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 2 individuals with LFS-associated cancers totaling 4 phenotype points (PS2; PMID: 22233476, 32658383). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1, PS2, PM2_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024).
Labcorp Genetics (formerly Invitae), Labcorp RCV000541004 SCV000629807 pathogenic Li-Fraumeni syndrome 2023-09-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys124*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with childhood adrenocortical carcinoma (PMID: 22233476). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 458537). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc. RCV004023787 SCV004933347 pathogenic Li-Fraumeni syndrome 1 2024-02-13 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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