ClinVar Miner

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

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000526324 SCV001142560 pathogenic Li-Fraumeni syndrome 2019-08-28 reviewed by expert panel curation This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in at least 2 probands meeting Chompret criteria (PS4_Supporting; PMID: 21601526, 8164043). Additionally, there is one proband with a de novo observation of a Li-Fraumeni syndrome core cancer under the age of 5 years with parental confirmation (PS2_Moderate; PMID: 19556618). In summary, the clinical significance of TP53 c.488A>G; p.Tyr163Cys is pathogenic for Li-Fraumeni syndrome: PM2_Supporting, PP3_Moderate, PM1, PS3, PS4_Supporting, PS2_Moderate.
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).
Ambry Genetics RCV000492788 SCV000581096 pathogenic Hereditary cancer-predisposing syndrome 2017-05-08 criteria provided, single submitter clinical testing The p.Y163C variant (also known as c.488A>G), located in coding exon 4 of the TP53 gene, results from an A to G substitution at nucleotide position 488. The tyrosine at codon 163 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration is located in the functionally critical DNA binding domain of the p53 protein. In multiple yeast-based functional studies, this alteration has been shown to be devoid of transactivation capability and demonstrate dominant negative properties (Chappuis PO et al. Int. J. Cancer 1999 Dec;84(6):587-93; Kato S et al.Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Dearth LR et al. Carcinogenesis 2007 Feb;28(2):289-98; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). The p.Y163C variant was observed in an individual from a LFS family who was diagnosed with adrenocortical carcinoma at the age of 2.5 years and an anaplastic astrocymtoma at the age of 14 (Villani et. al. Lancet Oncology. 2011;12:559). In addition, this alteration has been observed as a germline alteration a patient with early onset osteosarcoma and a family history of central nervous system malignancies (McIntyre JF et al. J. Clin. Oncol. 1994 May;12(5):925-30). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000526324 SCV000629829 pathogenic Li-Fraumeni syndrome 2020-08-27 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.
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 carcinoma 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 Breast neoplasm 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
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785334 SCV000923902 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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