ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.518T>C (p.Val173Ala) (rs1057519747)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc 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 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 173 of the TP53 protein (p.Val173Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant 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). An experimental study in yeast has shown that this variant partially impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). A different missense substitution at this codon (p.Val173Met) has been determined to be pathogenic (PMID: 16494995, 21343334, 12826609, Invitae). This suggests that the valine residue is critical for TP53 protein function and that other missense substitutions at this position may also be damaging. For these reasons, this allele has been classified as 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 Adrenocortical 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 Adenocarcinoma of stomach 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

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