Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000464372 | SCV000545320 | likely pathogenic | Li-Fraumeni syndrome | 2023-05-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 249 of the TP53 protein (p.Arg249Ser). This variant is not present in population databases (gnomAD no frequency). 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: 9407971, 15982667, 16754663, 19913028, 20516128, 20538734, 22110706, 25131192). 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: 12352). This missense change has been observed in individual(s) with Li-Fraumeni Syndrome (PMID: 15982667). It has also been observed to segregate with disease in related individuals. |
Color Diagnostics, |
RCV000579519 | SCV000686767 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-08-16 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with serine at codon 249 of the TP53 protein. Codon 249 is a known mutational hotspot for somatic mutation in cancer (PMID: 15982667, 17311302, 19756158, 28412734, 33300245). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant to be defective in yeast-based transcriptional transactivation assays, and human cell proliferation and growth suppression assays (PMID: 12826609, 29979965, 30224644). This variant has been reported germline in individuals affected with early onset breast cancer (PMID: 30374176; Color internal data) and is reported at high frequency as a somatic mutation in Aflatoxin B1- and Hepatitis B virus-related hepatocellular carcinoma (PMID: 20182602, 30508182, 30608603). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
University of Washington Department of Laboratory Medicine, |
RCV000464372 | SCV000886463 | pathogenic | Li-Fraumeni syndrome | 2018-05-25 | criteria provided, single submitter | research | The TP53 variant designated as NM_000546.5:c.747G>T (p.Arg249Ser) is classified as pathogenic. This variant has not been reported in public population databases. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 7.52 to 1 that this allele explains cancer in the family (Thompson et al, 2003, PMID:2900794). Computer software programs (SIFT, Polyphen-2, PROVEAN) predict that this variant is likely to have a damaging effect. Experimental functional studies provide evidence that this variant can lead to loss of function by disrupting protein structure (Gouas et al, 2010, PMID: 20538734; Lee et al, 2008, PMID: 18477611; Butler et al, 2005, PMID: 15982667; Joerger et al, 2005, PMID: 15703170; Chan et al, 2004, PMID:15060172; Kato et al, 2003, PMID: 12826609; Bullock et al, 1997, PMID: 9405613). Additionally, analysis of breast tumor in one member of the observed family shows loss of heterozygosity for the allele with this TP53 variant in breast tissue, which adds moderate evidence that this variant is pathogenic. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 99% probability of pathogenicity, which is consistent with a classification of pathogenic. The combined results are consistent with a classification of pathogenic in the context of Li-Fraumeni syndrome. This variant is expected to alter TP53 function and increase risks related to Li-Fraumeni syndrome associated cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. |
Institute of Biochemistry, |
RCV001270276 | SCV001450493 | pathogenic | Squamous cell carcinoma of the head and neck | criteria provided, single submitter | case-control | ||
Gene |
RCV001562247 | SCV001784983 | pathogenic | not provided | 2024-08-14 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17332323, 16861262, 9627118, 20538734, 19366907, 23200676, 19376640, 24489544, 21869931, 23836507, 21768053, 22675488, 14741214, 19834951, 18477611, 22759751, 21445056, 27698932, 1349102, 1849234, 8174105, 7935394, 20407015, 27346245, 17344317, 10321740, 8843196, 15781620, 32475984, 15982667, 34282142, 20212049, 30224644, 19913028, 34326862, 34273903, 29979965, 15510160, 30374176) |
Ambry Genetics | RCV000579519 | SCV002669791 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-07-27 | criteria provided, single submitter | clinical testing | The p.R249S pathogenic mutation (also known as c.747G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 747. The arginine at codon 249 is replaced by serine, 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). Another alteration at the same codon, p.R249K (c.746G>A), has been detected in one child with adrenal cortical carcinoma (Ambry internal data). The p.R249S alteration was classified as pathogenic by one study that evaluated multiple lines of evidence, including population data, functional evidence, in silico prediction models, segregation with disease and clinical phenotype including tumor characteristics (Tsai GJ et al. Genet Med, 2019 06;21:1435-1442). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This alteration has also 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. |
Myriad Genetics, |
RCV004018617 | SCV004933142 | 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: 8001119, 8843196, 12509279, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. |
OMIM | RCV000013145 | SCV000033392 | pathogenic | Hepatocellular carcinoma | 1992-05-02 | no assertion criteria provided | literature only | |
OMIM | RCV000013146 | SCV000033393 | pathogenic | Cervical cancer | 1992-05-02 | no assertion criteria provided | literature only | |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785491 | SCV000924063 | likely pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research | |
University Health Network, |
RCV000785491 | SCV001738477 | likely pathogenic | Ovarian neoplasm | 2021-03-19 | no assertion criteria provided | clinical testing | |
Key Laboratory of Carcinogenesis and Cancer Invasion, |
RCV003996089 | SCV004046835 | likely pathogenic | Adrenal cortex carcinoma | no assertion criteria provided | clinical testing |