ClinVar Miner

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

dbSNP: rs1057519747
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 21
Download table as spreadsheet
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.
Invitae RCV001237773 SCV001410547 pathogenic Li-Fraumeni syndrome 2023-09-30 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. 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.
Database of Curated Mutations (DoCM) RCV000436282 SCV000504755 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445170 SCV000504756 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426247 SCV000504757 likely pathogenic Acute myeloid leukemia 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437348 SCV000504758 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419648 SCV000504759 likely pathogenic Adrenal cortex carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430804 SCV000504760 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437553 SCV000504761 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420735 SCV000504762 likely pathogenic Ovarian serous cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430991 SCV000504763 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438619 SCV000504764 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420982 SCV000504765 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428561 SCV000504766 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438785 SCV000504767 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421990 SCV000504768 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432237 SCV000504769 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439921 SCV000504770 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.