ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.488A>G (p.Tyr163Cys) (rs148924904)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492788 SCV000581096 pathogenic Hereditary cancer-predisposing syndrome 2017-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Database of Curated Mutations (DoCM) RCV000443742 SCV000510057 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423543 SCV000510058 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434251 SCV000510059 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443833 SCV000510060 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427698 SCV000510061 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434917 SCV000510062 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442798 SCV000510063 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424864 SCV000510064 likely pathogenic Small cell lung cancer 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435593 SCV000510065 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419946 SCV000510066 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430191 SCV000510067 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436926 SCV000510068 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419252 SCV000510069 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429510 SCV000510070 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
GeneDx RCV000115725 SCV000149634 pathogenic not provided 2017-12-08 criteria provided, single submitter clinical testing This variant is denoted TP53 c.488A>G at the cDNA level, p.Tyr163Cys (Y163C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAC>TGC) in exon 5. This mutation has been reported in a child with osteosarcoma, one with myelodysplastic syndrome and has been shown to nearly eliminate p53 function using a quantitative yeast-based assay (McIntyre 1994, Monti 2011, Villani 2011). This mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Mutation Server, indicating it is not a common benign mutation in these populations. This mutation is a non-conservative substitution of a neutral polar amino acid for a neutral polar one, altering a position that is well conserved throughout evolution and is located in the DNA interaction domain with HIPK1, ZNF385A, FOXO42 and AXIN1. Multiple in silico algorithms predict that this mutation may be damaging to protein structure and function. All available information suggests that TP53 Tyr163Cys is a pathogenic mutation. This variant has been seen apparently mosaic. The variant is found in HEREDICANCER panel(s).
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785334 SCV000923902 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000526324 SCV000629829 pathogenic Li-Fraumeni syndrome 2017-12-12 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 163 of the TP53 protein (p.Tyr163Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with childhood osteosarcoma, whose mother had brain cancer at 45 years old (PMID: 8164043). It has also been reported to be de novo in at least one individual affected with Li-Fraumeni-related cancers (PMID: 18685109, 19556618, 25584008). This variant has been observed in individuals with breast cancer (PMID: 11051239, 25757876). ClinVar contains an entry for this variant (Variation ID: 127814). Experimental studies have shown that this missense change has a dominant-negative effect over the wild-type TP53 protein and results in altered DNA binding and severe reduction of transactivation activity in yeast and mammalian-based functional assays (PMID: 12826609, 16861262, 21343334). For these reasons, this variant has been classified as Pathogenic.

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