Submissions for variant NM_000546.6(TP53):c.652G>A (p.Val218Met)

dbSNP: rs878854072

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228072	SCV000285205	pathogenic	Li-Fraumeni syndrome	2024-09-03	criteria provided, single submitter	clinical testing	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 (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 237952). Invitae Evidence Modeling incorporating data from in vitro 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.
Sema4, Sema4	RCV002256136	SCV002532698	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	curation
GeneDx	RCV001357802	SCV005327536	likely pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV002256136	SCV005951589	pathogenic	Hereditary cancer-predisposing syndrome	2024-12-30	criteria provided, single submitter	clinical testing	The p.V218M pathogenic mutation (also known as c.652G>A), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide position 652. The valine at codon 218 is replaced by methionine, an amino acid with highly similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc Natl Acad Sci U S A, 2003 Jul;100:8424-9). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357802	SCV001553386	uncertain significance	not provided		no assertion criteria provided	clinical testing	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.