Submissions for variant NM_000546.6(TP53):c.515T>A (p.Val172Asp)

dbSNP: rs1131691021

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001037957	SCV001201395	uncertain significance	Li-Fraumeni syndrome	2024-04-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 172 of the TP53 protein (p.Val172Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 836761). 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). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002337102	SCV002641346	likely pathogenic	Hereditary cancer-predisposing syndrome	2017-10-11	criteria provided, single submitter	clinical testing	The p.V172D variant (also known as c.515T>A), located in coding exon 4 of the TP53 gene, results from a T to A substitution at nucleotide position 515. The valine at codon 172 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant is located in the functionally critical DNA binding domain and showed loss of transactivation capacity in comparison to wild type in a yeast-based functional assay (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). A different alteration at this codon, p.V172F, was detected in a patient meeting classic Li-Fraumeni syndrome (LFS) criteria (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003396634	SCV004105574	uncertain significance	TP53-related disorder	2023-08-13	criteria provided, single submitter	clinical testing	The TP53 c.515T>A variant is predicted to result in the amino acid substitution p.Val172Asp. To our knowledge, this variant has not been reported as a germline variant in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. A yeast-based functional study showed that this variant possesses ~10.43% transcriptional activity compared to wild-type TP53 protein (Kato et al. 2003. PubMed ID: 12826609, data deposited in http://mutantp53.broadinstitute.org/?query=p.V172D). This variant has conflicting interpretations of pathogenicity in ClinVar ranging from likely pathogenic to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/836761). Different germline nucleotide substitutions affecting the same amino acid (p.Val172Ile, p.Val172Phe) have been reported in individuals with TP53-associated cancers (Sun et al. 2017. PubMed ID: 28724667; Table S3, Rana et al. 2019. PubMed ID: 31105275). Taken together, although we suspect that the c.515T>A (p.Val172Asp) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Myriad Genetics, Inc.	RCV004031050	SCV004930460	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].