rs121912651
Variant summary
Our verdict is Pathogenic. Variant got 25 ACMG points: 25P and 0B. PS3PS2PS4PM1PM5PP1_StrongPP3_ModeratePP4_ModeratePM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.742C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 248 (p.Arg248Trp). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with an LFS-associated cancer totaling four phenotype points (PS2; PMID:10089074). This variant has been reported in >10 unrelated probands meeting Classic and Revised Chompret criteria. Based on this evidence, this variant scores 13.5 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs: 8527048, 9242456, 20522432, 8425176, 32658383, 9825943, 1978757. Internal lab contributors: SCV000212766.7, SCV000218912.13). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses in six families (PP1_Strong; PMID:8527048, 9825943, 8527048, 1978757, 9825943, 9242456). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID:34906512, Internal lab contributors: SCV000212766.7). This variant has an allele frequency of 0.000005933 (7/1179814 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID:8023157 ) (PM1). Another missense variant c.743G>A; p.Arg248Gln (ClinVar Variation ID 12356), in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). Computational predictor scores (BayesDel = 0.5336; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4_Very Strong, PP1_Strong, PP4_Moderate, PM2_Supporting, PS3, PM1, PM5, PP3_Moderate. (Bayesian Points: 29; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000382/MONDO:0018875/009
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 0.835
Genes affected
TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 25 ACMG points.
PS2
For more information check the summary or visit ClinGen Evidence Repository.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM5
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TP53 | NM_000546.6 | c.742C>T | p.Arg248Trp | missense_variant | 7/11 | ENST00000269305.9 | NP_000537.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TP53 | ENST00000269305.9 | c.742C>T | p.Arg248Trp | missense_variant | 7/11 | 1 | NM_000546.6 | ENSP00000269305 | P1 |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 151940Hom.: 0 Cov.: 31 FAILED QC
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:58Uncertain:1Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:8
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 15, 1992 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Apr 01, 2022 | ACMG classification criteria: PS2 strong, PS3 strong, PS4 strong, PM1 moderated, PM2 moderated, PP1 strong, PP3 supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 09, 2021 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jan 10, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 11, 2023 | This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10089074, 9242456, 20522432]. Functional studies indicate this variant impacts protein function [PMID: 17417627, 14743206, 9150393, 8062826]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 25, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jun 21, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the TP53 protein (p.Arg248Trp). This variant is present in population databases (rs121912651, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and breast cancer (PMID: 1978757, 23172776, 23950206, 24573247). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12347) with 52 entries, all of which classify this variant as pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 20128691, 21343334, 23172776, 29979965, 30224644). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17606709, 20128691). Therefore, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic TP53 gene cause Li-Fraumeni syndrome. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Oct 13, 2023 | PS3, PS4, PS2 - |
Li-Fraumeni syndrome Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 27, 2023 | Variant summary: TP53 c.742C>T (p.Arg248Trp) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251490 control chromosomes. c.742C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome or other types of cancer. These data indicate that the variant is very likely to be associated with disease. At least two publication reports experimental evidence evaluating an impact on protein function and showed that this variant results in abrogation of Tp53 tumor suppressor activity (Fregourg_1992, Zerdoumi_2012). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the TP53 protein (p.Arg248Trp). This variant is present in population databases (rs121912651, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and breast cancer (PMID: 1978757, 23172776, 23950206, 24573247). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12347). 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, 17606709, 20128691, 21343334, 23172776, 29979965, 30224644). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17606709, 20128691). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 10, 2020 | proposed classification - variant undergoing re-assessment, contact laboratory - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Pathogenic, reviewed by expert panel | curation | ClinGen TP53 Variant Curation Expert Panel, ClinGen | Aug 05, 2024 | The NM_000546.6: c.742C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 248 (p.Arg248Trp). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with an LFS-associated cancer totaling four phenotype points (PS2; PMID: 10089074). This variant has been reported in >10 unrelated probands meeting Classic and Revised Chompret criteria. Based on this evidence, this variant scores 13.5 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs: 8527048, 9242456, 20522432, 8425176, 32658383, 9825943, 1978757. Internal lab contributors: SCV000212766.7, SCV000218912.13). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses in six families (PP1_Strong; PMID: 8527048, 9825943, 8527048, 1978757, 9825943, 9242456). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors: SCV000212766.7). This variant has an allele frequency of 0.000005933 (7/1179814 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Another missense variant c.743G>A; p.Arg248Gln (ClinVar Variation ID 12356), in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). Computational predictor scores (BayesDel = 0.5336; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4_Very Strong, PP1_Strong, PP4_Moderate, PM2_Supporting, PS3, PM1, PM5, PP3_Moderate. (Bayesian Points: 29; VCEP specifications version 2.0; 7/24/2024) - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 24, 2023 | This missense variant replaces arginine with tryptophan at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant occurs at an established tumor hotspot in the TP53 protein (PMID: 20182602, 26619011). Functional studies have shown that this variant is defective for DNA binding and transcriptional transactivation of TP53 target genes, displays loss of function and dominant negative activity in human cell growth suppression assays and is non-functional in human cell proliferation assays (PMID: 12826609, 17417627, 20013323, 21343334, 23172776, 28369373, 29979965, 30224644). This variant has been reported in individuals affected with Li Fraumeni syndrome cancers (PMID: 1978757, 1631137, 8425176, 9598730, 17606709, 17427234, 20522432, 23172776, 23667202, 23950206, 27374712, 28369373). It has been shown that this variant segregates with disease in Li Fraumeni families (PMID: 1978757, 8527048, 9242456, 9825943) and has been observed to occur de novo (PMID: 10089074, 29025599). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 11, 2022 | Observed in several individuals and families meeting Li-Fraumeni or Li-Fraumeni like criteria (Malkin et al., 1990, Birch et al., 1994, Hwang et al., 2003, Monti et al., 2007, Rossbach et al., 2008, Serra et al., 2013, Villani et al., 2016); Published functional studies demonstrate a damaging effect: non-functional transactivation, dominant-negative effect, loss of growth suppression activity (Kato et al., 2003, Willis et al., 2004, Grochova et al., 2008, Monti et al., 2011, Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8118819, 27501770, 26215675, 1978757, 12209590, 12610779, 27374712, 24603336, 16959974, 28387325, 28527674, 29979965, 25525159, 19378321, 30076369, 29324801, 20128691, 15280671, 17606709, 17724467, 14743206, 1565144, 25925845, 24651015, 26787237, 27714481, 22265402, 23950206, 9764816, 17427234, 27323394, 26223322, 25958320, 26703669, 23172776, 24573247, 21343334, 26681312, 28831167, 29025599, 28369373, 29077933, 28915717, 28356770, 28735817, 28624650, 29489754, 29730572, 30042819, 11051239, 28472496, 28724667, 29752822, 30092803, 29753700, 29961768, 30720243, 21686767, 31016814, 30840781, 30137042, 31081129, 15510160, 12826609, 29625052, 31105275, 31447099, 31775759, 32930885, 33818021, 32475984, 33300245, 30755392, 32658383, 32817165, 33245408, 33087929) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 25, 2019 | The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. One de novo case with parental identity not confirmed. - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Ovarian neoplasm Pathogenic:2
| Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | University Health Network, Princess Margaret Cancer Centre | Mar 19, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2022 | The p.R248W pathogenic mutation (also known as c.742C>T), located in coding exon 6 of the TP53 gene, results from a C to T substitution at nucleotide position 742. The arginine at codon 248 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in many individuals and families from various ethnicities affected with Li-Fraumeni syndrome-associated cancers (Malkin D et al. Science. 1990 Nov 30;250(4985):1233-8; Bang YJ et al. J. Korean Med. Sci. 1995 Jun;10:205-10; Alsner J et al. Clin Cancer Res. 2000 Oct;6(10):3923-31; Andrade RC et al. Pediatr Blood Cancer. 2013 Sep 13; Rieber J et al. Genes Chromosomes Cancer. 2009 Jul; 48(7):558-68; Arcand SL et al. BMC Med. Genet. 2015 Apr;16:24; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). This mutation was also reported in an individual diagnosed with bilateral breast cancer at ages 29 and 34; in vitro studies showed significantly reduced induction levels of TP53 target genes in LFS lymphocytes that had been exposed to DNA damage resulting in greatly reduced cellular response to DNA damage (Zerdoumi Y et al. Hum Mutat. 2013 Mar;34(3):453-61). 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). In another study, a functional protein microarray indicated that TP53 polypeptide with p.R248W alteration exhibited less than 40% DNA binding activity compared to wild type protein (Malcikova J et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 12, 2023 | This missense variant replaces arginine with tryptophan at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant occurs at an established tumor hotspot in the TP53 protein (PMID: 20182602, 26619011). Functional studies have shown that this variant is defective for DNA binding and transcriptional transactivation of TP53 target genes, displays loss of function and dominant negative activity in human cell growth suppression assays and is non-functional in human cell proliferation assays (PMID: 12826609, 17417627, 20013323, 21343334, 23172776, 28369373, 29979965, 30224644). This variant has been reported in individuals affected with Li Fraumeni syndrome cancers (PMID: 1978757, 1631137, 8425176, 9598730, 17606709, 17427234, 20522432, 23172776, 23667202, 23950206, 27374712, 28369373). It has been shown that this variant segregates with disease in Li Fraumeni families (PMID: 1978757, 8527048, 9242456, 9825943) and has been observed to occur de novo (PMID: 10089074, 29025599). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Neoplasm Pathogenic:1Other:1
| -, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Myelodysplastic syndrome Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Glioblastoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Prostate adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Carcinoma of esophagus Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell carcinoma of the skin Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Gastric adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Acute myeloid leukemia;C0030312:Pancytopenia;C0221217:Webbed neck;C0338656:Cognitive impairment;C0349588:Short stature;C0878638:Abnormality of the tongue;C2051831:Pectus excavatum Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | - | - - |
Squamous cell lung carcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Breast neoplasm Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Choroid plexus carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Michigan Center for Translational Pathology, University of Michigan | Dec 22, 2020 | - - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Brainstem glioma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Adrenocortical carcinoma, hereditary Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 16, 2023 | - - |
Multiple myeloma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of brain Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Hepatocellular carcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of the large intestine Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Small cell lung carcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 07, 2021 | - - |
Malignant lymphoma, large B-cell, diffuse Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Wasik Lab, Fox Chase Cancer Center | Jul 25, 2023 | This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. TP53 tumor suppressor dysregulation is associated with partial or no response to CHOP-based chemotherapy (Young et al. 2007; Xu-Monette et al. 2012). TP53 mutations frequently involve the DNA binding domain, exons 5-8, impairing TP53 mediated transcriptional transactivation (Miao et al. 2019). TP53 R248W was detected in this tumor at presentation and recurrence, and is predicted to cause structural defects in the region responsible for DNA binding. Genomic DNA copy number assays indicated the normal TP53 allele was lost at relapse. TP53 mutation is uncommon in the MYD88 cluster of DLBCL but when present, it confers an extremely poor prognosis (Lacy et al. 2020). - |
Medulloblastoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Ovarian serous cystadenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Malignant melanoma of skin Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Uterine carcinosarcoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Lip and oral cavity carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Institute of Medical Sciences, Banaras Hindu University | Apr 30, 2019 | - - |
Acute myeloid leukemia Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
B-cell chronic lymphocytic leukemia Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Malignant neoplasm of body of uterus Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Pancreatic adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Congenital fibrosarcoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | May 10, 2022 | - - |
Lung adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Transitional cell carcinoma of the bladder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
TP53-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 09, 2024 | The TP53 c.742C>T variant is predicted to result in the amino acid substitution p.Arg248Trp. This variant has been reported in multiple individuals with Li-Fraumeni syndrome and breast cancer and has been observed to segregate with disease in related individuals (Malkin et al. 1990. PubMed ID: 1978757; Zerdoumi et al. 2013. PubMed ID: 23172776; Brugières et al. 1993. PubMed ID: 8425176; Varley et al. 1997. PubMed ID: 9242456). This variant is in a codon (p.Arg248) that is an established mutational hotspot (Olivier et al. 2010. PMID: 20182602) and functional studies demonstrate that this variant impacts protein function (Kato et al. 2003. PubMed ID: 12826609; Giacomelli et al. 2018. PubMed ID: 30224644; Kotler et al. 2018. PubMed ID: 29979965). An alternate nucleotide change affecting the same amino acid (p.Arg248Gln), has been reported in individuals with TP53-related conditions (Varley et al. 1997. PubMed ID: 9242456). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12347/). This variant is interpreted as pathogenic. - |
Squamous cell carcinoma of the head and neck Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Gallbladder cancer Uncertain:1
| Uncertain significance, no assertion criteria provided | research | Institute of Medical Sciences, Banaras Hindu University | Oct 30, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;T;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
MutationTaster
Benign
A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen
D;.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D
Vest4
MutPred
Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);.;.;.;.;.;.;.;Loss of disorder (P = 0.0612);.;Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);.;.;Loss of disorder (P = 0.0612);.;.;.;.;
MVP
MPC
0.39
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at