Submissions for variant NM_000546.6(TP53):c.518T>C (p.Val173Ala)

dbSNP: rs1057519747

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000775880	SCV000910358	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-01-14	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 173 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be partially functional in transactivation assays (PMID: 12826609) and non-functional in human cell growth assays (PMID: 29979965, 30224644). This variant has been reported to be de novo in an individuals affected with rhabdomyosarcoma and osteosarcoma, meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 29070607). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same amino acid position, p.Val173Met, is known to be disease-causing, (ClinVar variation ID: 233951), indicating that valine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001237773	SCV001410547	pathogenic	Li-Fraumeni syndrome	2024-05-15	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 173 of the TP53 protein (p.Val173Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteosarcoma and rhabdomyosarcoma (PMID: 29070607). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376017). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609). This variant disrupts the p.Val173 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 16494995, 21343334; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000775880	SCV002582386	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289516	SCV002583048	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000775880	SCV004093345	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-15	criteria provided, single submitter	clinical testing	The p.V173A variant (also known as c.518T>C), located in coding exon 4 of the TP53 gene, results from a T to C substitution at nucleotide position 518. The valine at codon 173 is replaced by alanine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with a rhabdomyosarcoma (Pondrom M et al. Pediatr Blood Cancer, 2020 Sep;67:e28486). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). Two other alterations at the same codon, p.V173L (c.517G>T) and p.V173M (c.517G>A), have been identified in an individual with a clinical diagnosis of Li-Fraumeni Syndrome and are deleterious based on multiple functional studies (Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Achatz M et al. Cancer Lett. 2007 Jan; 245(1-2):96-102; Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.