ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.722C>G (p.Ser241Cys)

dbSNP: rs28934573
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Total submissions: 26
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236210 SCV000293500 likely pathogenic not provided 2018-04-10 criteria provided, single submitter clinical testing This variant is denoted TP53 c.722C>G at the cDNA level, p.Ser241Cys (S241C) at the protein level, and results in the change of a Serine to a Cysteine (TCC>TGC). This variant has not, to our knowledge, been reported as a germline variant; however it has been reported as a somatic variant in multiple different tumor types (Laframboise 2000, Powell 2000, Koul 2002, Jordan 2010, COSMIC). This variant has also been reported as having non-functional transactivation activity in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003), and also demonstrated loss of transactivation capacity in a yeast functional assay (Jordan 2010). TP53 Ser241Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Ser241Cys occurs at a position that is conserved across species and is located in the DNA binding domain and the region of interaction with CCAR2, HIPK1, and AXIN1 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider TP53 Ser241Cys to be a likely pathogenic variant.
Ambry Genetics RCV000492778 SCV000581139 pathogenic Hereditary cancer-predisposing syndrome 2021-07-23 criteria provided, single submitter clinical testing The p.S241C pathogenic mutation (also known as c.722C>G), located in coding exon 6 of the TP53 gene, results from a C to G substitution at nucleotide position 722. The serine at codon 241 is replaced by cysteine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast-based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). 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 mutation has been identified in a family meeting classic Li-Fraumeni syndrome criteria (Sejben A et al. Orv Hetil 2019 Feb;160(6):228-234). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab RCV000492778 SCV002582363 likely pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002288664 SCV002583024 likely pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
Invitae RCV000154419 SCV003253335 likely pathogenic Li-Fraumeni syndrome 2023-05-01 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 241 of the TP53 protein (p.Ser241Cys). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 177791). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 30730202). This variant is not present in population databases (gnomAD no frequency).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000154419 SCV000204087 likely pathogenic Li-Fraumeni syndrome 2008-01-03 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000431373 SCV000509724 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442616 SCV000509725 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425780 SCV000509726 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432564 SCV000509727 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442642 SCV000509728 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426900 SCV000509729 likely pathogenic Papillary renal cell carcinoma, sporadic 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437089 SCV000509730 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419417 SCV000509731 likely pathogenic Ovarian serous cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426195 SCV000509732 likely pathogenic Papillary renal cell carcinoma type 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438178 SCV000509733 likely pathogenic Uterine carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420364 SCV000509734 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430604 SCV000509735 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439098 SCV000509736 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417965 SCV000509737 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428236 SCV000509738 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438488 SCV000509739 likely pathogenic Non-Hodgkin lymphoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422573 SCV000509740 likely pathogenic Gallbladder carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429339 SCV000509741 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439590 SCV000509742 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785321 SCV000923889 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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