17-7674879-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The ENST00000269305.9(TP53):c.652G>A(p.Val218Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V218G) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000269305.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.652G>A | p.Val218Met | missense_variant | 6/11 | ENST00000269305.9 | NP_000537.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.652G>A | p.Val218Met | missense_variant | 6/11 | 1 | NM_000546.6 | ENSP00000269305 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The TP53 p.Val218Met variant was identified in 1 of 346 proband chromosomes (frequency: 0.003) from Chinese individuals or families with CLL (chronic lymphocytic leukemia) (Dong 2011). The variant was also identified in a brain tumor (Ryzhova 2017). Application of evolutionary prediction using a codon-based maximum likelihood model estimating the selective pressures on individual amino acid residues, suggest the presence of strong selective constraints on the variant, indicating structural relevance or direct association with DNA (Arbiza 2006). In a study using site-directed mutageneisis and a yeast based functional assay evaluating all possible TP53 amino acid substitutions resulting from point mutations, the variant localized to a functionally defined DNA-binding domain (residuesrn96–286) which corresponds well to the proteolysis-resistant and structurallyrncompact core domain (subtilisin fragment, residues 102–292) (Kato 2003). The variant was also identified in dbSNP (ID: rs878854072) “With Uncertain significance allele”, and ClinVar (classified pathogenic by Invitae), while not identified in LOVD 3.0 or UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Val218 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Met variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate non-functional transactivation and retained growth suppression abilities (Kato et al., 2003; Kotler et al., 2018; Giacomelli et al., 2018); This variant is associated with the following publications: (PMID: 30840781, 15510160, 30224644, 29979965, 12826609, 28400619, 27892470, 34878101, 30661751, 32371905, 26580448) - |
Li-Fraumeni syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 24, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 218 of the TP53 protein (p.Val218Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adrenocortical carcinoma (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 237952). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 29, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at