ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.722C>T (p.Ser241Phe) (rs28934573)

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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130168 SCV000185004 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-02 criteria provided, single submitter clinical testing The p.S241F variant (also known as c.722C>T), located in coding exon 6 of the TP53 gene, results from a C to T substitution at nucleotide position 722. The serine at codon 241 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant has been identified in 2 individuals diagnosed in childhood with multiple tumors belonging to the Li-Fraumeni syndrome tumor spectrum, including osteosarcoma and tumors of the liver (Toguchida J et al. N. Engl. J. Med. 1992 May;326:1301-8; Gonzalez KD et al. J. Med. Genet. 2009 Oct;46:689-93). Functional studies of this alteration have demonstrated a significant decrease in DNA binding and absence of transactivation ability (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Clin. Cancer Res. 2007 Jul;13:3789-95, Malcikova J et al. Biol. Chem. 2010;391:197-205), as well as a dominant negative effect on the wild-type protein (Brachmann RK et al. Proc. Natl. Acad. Sci. U.S.A. 1996 Apr;93(9):4091-5; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (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 on sequence alignment. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000559355 SCV000629860 likely pathogenic Li-Fraumeni syndrome 2019-12-22 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 241 of the TP53 protein (p.Ser241Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been shown to arise likely de novo in an individual affected with osteosarcoma and hepatoblasoma (PMID: 1565143). It has also been observed in another individual affected with osteosarcoma, without parental testing performed (PMID: 23031740), as well as in individuals affected with breast and/or ovarian cancer, and colorectal cancer (PMID: 26911350, 28975465). ClinVar contains an entry for this variant (Variation ID: 12359). Experimental studies have shown that this missense change disrupts transactivation and DNA binding activities (PMID: 20128691, 21343334, 26585234, 12826609). 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.
OMIM RCV000013153 SCV000033400 pathogenic Hepatoblastoma 1993-01-01 no assertion criteria provided literature only
OMIM RCV000013154 SCV000033401 pathogenic Osteosarcoma 1993-01-01 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426268 SCV000509686 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436959 SCV000509687 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444801 SCV000509688 likely pathogenic Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426907 SCV000509689 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435867 SCV000509690 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418653 SCV000509691 likely pathogenic Non-Hodgkin lymphoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429321 SCV000509692 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436527 SCV000509693 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417576 SCV000509694 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428255 SCV000509695 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438965 SCV000509696 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421750 SCV000509697 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430665 SCV000509698 likely pathogenic Papillary renal cell carcinoma, sporadic 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441398 SCV000509699 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422867 SCV000509700 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433125 SCV000509701 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441622 SCV000509702 likely pathogenic Carcinoma of gallbladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423921 SCV000509703 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434173 SCV000509704 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785290 SCV000923858 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Institute of Medical Sciences, Banaras Hindu University RCV001255673 SCV001432238 pathogenic Lip and oral cavity carcinoma 2019-04-30 no assertion criteria provided research

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