Total submissions: 27
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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- |
RCV000492778 | SCV002582363 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Genome- |
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). |
Myriad Genetics, |
RCV002288664 | SCV004932198 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-16 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. |
Laboratory for Molecular Medicine, |
RCV000154419 | SCV000204087 | likely pathogenic | Li-Fraumeni syndrome | 2008-01-03 | no assertion criteria provided | clinical testing | |
Database of Curated Mutations |
RCV000431373 | SCV000509724 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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 |
RCV000425780 | SCV000509726 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432564 | SCV000509727 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442642 | SCV000509728 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426900 | SCV000509729 | likely pathogenic | Papillary renal cell carcinoma, sporadic | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437089 | SCV000509730 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419417 | SCV000509731 | likely pathogenic | Ovarian serous cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426195 | SCV000509732 | likely pathogenic | Papillary renal cell carcinoma type 1 | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438178 | SCV000509733 | likely pathogenic | Uterine carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420364 | SCV000509734 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430604 | SCV000509735 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439098 | SCV000509736 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417965 | SCV000509737 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428236 | SCV000509738 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438488 | SCV000509739 | likely pathogenic | Non-Hodgkin lymphoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422573 | SCV000509740 | likely pathogenic | Gallbladder carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429339 | SCV000509741 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439590 | SCV000509742 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785321 | SCV000923889 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |