Submissions for variant NM_000546.6(TP53):c.722C>T (p.Ser241Phe)

dbSNP: rs28934573

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130168	SCV000185004	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-15	criteria provided, single submitter	clinical testing	The p.S241F pathogenic mutation (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 mutation has been identified in multiple individuals diagnosed during childhood with tumors belonging to the Li-Fraumeni syndrome tumor spectrum (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; Osumi T et al. Pediatr Blood Cancer. 2012 Dec;59:1332-3; Renaux-Petel M et al. J Med Genet. 2018 03;55:173-180). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Brachmann RK et al. Proc. Natl. Acad. Sci. U.S.A. 1996 Apr;93:4091-5; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Malcikova J et al. Biol Chem. 2010 391:197-205). 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). Two other alterations at the same codon, p.S241C (c.722C>G) and p.S241A (c.721T>G), have been described to also have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9) and to be deficient at growth suppression with 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 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.
Invitae	RCV000559355	SCV000629860	pathogenic	Li-Fraumeni syndrome	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 241 of the TP53 protein (p.Ser241Phe). This variant is present in population databases (rs28934573, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni (PMID: 1565143, 23031740). ClinVar contains an entry for this variant (Variation ID: 12359). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20128691, 21343334, 26585234, 29979965, 30224644). This variant disrupts the p.Ser241 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 23259501, 25584008, 28279309, 30224644). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000130168	SCV002582364	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288485	SCV002583025	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496336	SCV002810992	likely pathogenic	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5	2022-04-22	criteria provided, single submitter	clinical testing
GeneDx	RCV003114189	SCV003798846	pathogenic	not provided	2022-08-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: impaired DNA binding and transcriptional activation (Malcikova et al., 2010; Kotler et al., 2018); Observed in individuals with TP53-related cancers (Toguchida et al., 1992; Gonzalez et al., 2009; Mannan et al., 2016; Kwong et al., 2020); This variant is associated with the following publications: (PMID: 21343334, 1565143, 17606709, 23031740, 30840781, 31105275, 19225112, 26585234, 20128691, 29979965, 22887876, 32475984, 15510160, 33087929, 30720243, 26911350, 33138793, 28975465, 19556618, 29070607, 32817165)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003114189	SCV004221371	pathogenic	not provided	2022-09-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251476 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with Li-Fraumeni syndrome (LFS) (PMIDs: 17606709 (2007), 23031740 (2012), 26911350 (2016), 28975465 (2017), and 32817165 (2020)). Functional studies demonstrated decreased DNA binding, transactivation activity, a dominant negative effect, and reduced solubility compared to wild type (PMIDs: 8633021 (1996), 20128691 (2010), 21343334 (2011), 29979965 (2018), 30224644 (2018), 32475984 (2020)). Three de novo cases have been identified (PMIDs: 1565143 (1992), 19556618 (2009), and 22887876 (2012)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV002288485	SCV004932244	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 1565143, 20586629]. This variant is expected to disrupt protein structure [Myriad internal data].
OMIM	RCV000013153	SCV000033400	pathogenic	Hepatoblastoma	1993-01-01	no assertion criteria provided	literature only
OMIM	RCV000013154	SCV000033401	pathogenic	Bone 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	Papillary renal cell carcinoma type 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	Gallbladder carcinoma	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, 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