rs1555526478
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS2PVS1PM2_Supporting
This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA397844214/MONDO:0018875/009
Frequency
Consequence
NM_000546.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.372C>A | p.Cys124Ter | stop_gained | 4/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.372C>A | p.Cys124Ter | stop_gained | 4/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2023 | 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. - |
Pathogenic, reviewed by expert panel | curation | ClinGen TP53 Variant Curation Expert Panel, ClinGen | Aug 28, 2019 | The p.Cys124* variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is a de novo observation of a proband with adrenocortical carcinoma in childhood without mention of parental confirmation (PM6; PMID: 22233476). In summary, TP53 c.372C>A; p.Cys124* meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PVS1, PM2_Supporting, PM6. - |
Li-Fraumeni syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 13, 2024 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at