17-7674220-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS3PS2PS4PM1PP1_ModeratePP4_ModeratePP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.743G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 248 (p.Arg248Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer, and in 1 individual with a moderately LFS-associated cancer totaling 7 phenotype points (PS2; PMIDs, 15381368; 35974385; 1565143). This variant has been reported in an additional two unrelated probands meeting Classic and seven probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMID:9242456, 7887414, 36457625, 21601526, ClinVar SCV SCV000185472.8, Internal lab contributor). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in four families (PP1_Moderate; PMID:1565143, 9242456, 7887414, 36457625). 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, ClinVar GTRs, Internal lab contributors). This variant has an allele frequency of 0.000007629 (9/1179752 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). Computational predictor scores (BayesDel = 0.4738; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). 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, PP1_Moderate, PP4_Moderate, PS3, PM1, PM2_Supporting, PP3. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000387/MONDO:0018875/009
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 6.16
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 20 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.
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.743G>A | p.Arg248Gln | 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.743G>A | p.Arg248Gln | missense_variant | 7/11 | 1 | NM_000546.6 | ENSP00000269305 | P1 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 151938Hom.: 0 Cov.: 31
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GnomAD4 genome 0.0000197 AC: 3AN: 151938Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74214
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:68Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 03, 2021 | Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression and apoptotic activities, dominant-negative effect (Lomax et al., 1998; Kato et al., 2003; Dearth et al., 2007; Monti et al., 2011; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 25637381, 24573247, 23334668, 21305319, 9704930, 15004724, 7718482, 12124823, 15541116, 9738975, 16322298, 8252037, 17606709, 22851211, 2263646, 26787237, 29300620, 29489754, 20128691, 21343334, 22110706, 24651015, 21761402, 19367569, 18048389, 8080050, 16861262, 18555592, 10557074, 10567903, 10914716, 16142349, 8707423, 10519380, 12917626, 10753186, 8062826, 7682763, 1915267, 7478555, 16959974, 12509970, 26703669, 28154273, 27153395, 26822237, 28724667, 28369373, 28125075, 29979965, 29478780, 28861920, 23538418, 30076369, 29752822, 26556299, 28975465, 29753700, 30092803, 30720243, 30093976, 30840781, 30553995, 31159747, 31081129, 19012332, 1565143, 25612911, 21601526, 7887414, 24810334, 27683180, 30709875, 15510160, 21552135, 1458490, 16778209, 10754498, 12826609, 31105275, 31447099, 32029870, 33818021, 33300245, 31851316, 32658383, 30982232, 33245408, 30875412, 32427313, 33674644) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | TP53: PP1:Strong, PM1, PM2, PM5, PS3:Moderate, PS4:Supporting - |
| Pathogenic, flagged submission | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Feb 02, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 09, 2023 | The frequency of this variant in the general population, 0.000026 (3/113756 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple Li-Fraumeni syndrome families (PMID: 21305319 (2011), 21601526 (2011), 17606709 (2007), 7887414 (1995), 1565143 (1992), 9242456 (1997)), as well as in individuals with breast cancer (PMID: 30287823 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/TP53)). Additionally, this variant has been shown to affect DNA binding and transactivation activities (PMID: 21343334 (2011), 20128691 (2010), 17606709 (2007)), as well as shown to have a dominant negative effect (PMID: 30224644 (2018)). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 09, 2014 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jun 25, 2018 | - - |
Li-Fraumeni syndrome 1 Pathogenic:7
| Pathogenic, no assertion criteria provided | research | Donald Williams Parsons Laboratory, Baylor College of Medicine | Dec 27, 2012 | This variant has been previously reported as disease-causing and was found once in our study maternally inherited in a 2-year-old female with neuroblastoma, in a family meeting criteria for Li-Fraumeni (history of early breast, brain tumors, rhabdomyosarcoma). - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 15, 2000 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 12, 2023 | This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15381368, 1565143, 8118819, 7887414]. Functional studies indicate this variant impacts protein function [PMID: 8023157, 10411893, 23538418, 21445056]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Feb 17, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 27, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12826609, 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012356 / PMID: 1565143). The variant has been previously reported as de novo in a similarly affected individual (PMID: 15381368). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15381368, 1565143, 7887414, 9242456). Different missense changes at the same codon (p.Arg248Gly, p.Arg248Leu, p.Arg248Pro, p.Arg248Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012347, VCV000230253, VCV000237954, VCV000376652, VCV000437017 / PMID: 11180592, 1978757, 28152038, 31105275). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 01, 2022 | This missense variant replaces arginine with glutamine 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). Functional studies have shown the mutant protein to be non-functional in DNA binding and transactivation assays (PMID: 9704930, 12826609, 20128691, 21343334, 23538418, 28369373), and defective in cell growth inhibition, apoptosis, and proliferation assays (PMID: 9704930, 21187651, 29979965, 30224644). This variant has been reported in numerous individuals affected with Li-Fraumeni syndrome (PMID: 1565143, 1683921, 7887414, 9242456, 10797439, 11139324, 11479205, 17606709, 18511570, 19556618, 21305319, 21552135, 21601526, 25612911, 26822237, 27683180 ) and breast cancer (PMID: 11139324, 16489069, 21761402, 30287823, 32000721, 33471991). It also has been observed de novo in Li Fraumeni patients with paternity confirmed (PMID: 15381368, 24810334). This variant has been identified in 3/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This sequence change replaces Arginine with Glutamine at codon 248 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein. There is a small physiochemical difference between arginine and glutamine (Grantham Score 43).This variant is present in population databases at a very low frequency (rs11540652, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 17606709, 21601526).Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. Moreover, experimental studies have shown that this missense change severely affects the functional activity of the p53 protein. This variant is classified as a severe deficiency allele with possible dominant-negative inhibitory effects (PMID: 21343334, 17606709, 20128691). The mutation database Clinvar contains entries for this variant (Variation ID:12356). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 28, 2021 | The p.R248Q (also known as c.743G>A) pathogenic mutation is located in coding exon 6 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 743. The arginine at codon 248 is replaced by glutamine, an amino acid with some similar properties. This alteration has been described as a de novo mutation in a woman with multiple primary osteosarcomas and bilateral breast cancer and her daughter with childhood-onset sarcoma (Toguchida J et al. N Engl J Med. 1992 May 14;326(20):1301-8). 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 alteration has been shown to be involved in DNA binding through crystal structure analysis (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). To date, this alteration has been detected in numerous LFS families and other pathogenic missense mutations at codon 248 have been reported (Petitjean A et al. IARC TP53 database [version R15, November 2010]. Hum Mutat. 2007 Jun;28(6):622-9; Stenson et al. The Human Gene Mutation Database (HGMD®): 2003 Update. Hum Mutat. 2003;21:577-581). Based on the available evidence, this alteration is classified as a pathogenic mutation. - |
Li-Fraumeni syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 20, 2019 | Variant summary: TP53 c.743G>A (p.Arg248Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes (gnomAD). c.743G>A has been reported in the literature in multiple individuals/families affected with Li-Fraumeni or Li-Fraumeni-like syndromes (e.g. Haque_2018, Rapakko_2001, Vahteristo_2001, Villani_2011) while, it was also reported in a LFS patient with a suggested de novo occurrence (Bendig_2004). These data indicate that the variant is very likely to be associated with disease. Functional studies demonstrate that the R248Q substitution impairs the DNA binding capability of TP53 essential for its tumor suppressor function (Merabet_2010), and the variant exhibited less than 25% of wild-type transcriptional transactivation activity. Additional studies have classified this variant as a severe deficiency allele with a dominant negative effect (Monti_2011, Zerdoumi_2017). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely 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 25, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 248 of the TP53 protein (p.Arg248Gln). This variant is present in population databases (rs11540652, gnomAD 0.006%). This missense change has been observed in individual(s) with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 7887414, 17606709, 21305319, 21601526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12356). 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: 17606709, 20128691, 21343334). 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: 8062826, 9546439, 12826609, 15722483; Invitae). 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 | Nov 23, 2011 | The Arg248Gln is a recurrent variant in TP53 which has been reported in more than 10 individuals with Li-Fraumeni syndrome (LFS; Santibanez-Koref 1991, Toguchida 1992, Frebourg 1995, Marsciari 2011, Villani 2011, Wu 2011, IARC TP53 Database). This variant shows moderate segration with disease among affected family members (>5 meiosis) and was absent from over 400 control choromosomes (Toguchida, 1992). In addition this variant is predicited to create a new splice site which could disrupt protein function or lead to absent protein (Kouidou 2009). Based on this information, this variant is highly likely to be pathogenic. - |
| Pathogenic, reviewed by expert panel | curation | ClinGen TP53 Variant Curation Expert Panel, ClinGen | Aug 05, 2024 | The NM_000546.6: c.743G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 248 (p.Arg248Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer, and in 1 individual with a moderately LFS-associated cancer totaling 7 phenotype points (PS2; PMIDs, 15381368; 35974385; 1565143). This variant has been reported in an additional two unrelated probands meeting Classic and seven probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMID: 9242456, 7887414, 36457625, 21601526, ClinVar SCV SCV000185472.8, Internal lab contributor). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in four families (PP1_Moderate; PMID: 1565143, 9242456, 7887414, 36457625). 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, ClinVar GTRs, Internal lab contributors). This variant has an allele frequency of 0.000007629 (9/1179752 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). Computational predictor scores (BayesDel = 0.4738; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). 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, PP1_Moderate, PP4_Moderate, PS3, PM1, PM2_Supporting, PP3. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Familial cancer of breast Pathogenic:2
| Pathogenic, criteria provided, single submitter | case-control | Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | University Health Network, Princess Margaret Cancer Centre | Mar 19, 2021 | - - |
Multiple myeloma Pathogenic:2
| Likely pathogenic, no assertion criteria provided | clinical testing | Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center | Aug 31, 2019 | - - |
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm Pathogenic:1Other:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
| -, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
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 | - - |
Adrenal cortex carcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University | - | - - |
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 | - - |
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 | - - |
Malignant tumor of urinary bladder Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory of Urology, Hospital Clinic de Barcelona | - | - - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0585442:Bone osteosarcoma;C0699790:Carcinoma of colon;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Ovarian neoplasm Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Brainstem glioma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Breast carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 08, 2021 | - - |
Adrenocortical carcinoma, hereditary Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 20, 2023 | - - |
Colorectal cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Genome Sciences Centre, British Columbia Cancer Agency | Apr 12, 2016 | - - |
Neoplasm of brain 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 | - - |
Hepatocellular carcinoma 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 | - - |
Rhabdomyosarcoma Pathogenic:1
| Pathogenic, no assertion criteria provided | provider interpretation | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Sep 01, 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 | - - |
Lip and oral cavity carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Institute of Medical Sciences, Banaras Hindu University | Apr 30, 2019 | - - |
Uterine carcinosarcoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Acute myeloid leukemia Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Ductal carcinoma in situ Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | University Health Network, Princess Margaret Cancer Centre | Mar 19, 2021 | - - |
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 | - - |
Lung adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Lymphoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center | Jul 25, 2019 | - - |
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.743G>A variant is predicted to result in the amino acid substitution p.Arg248Gln. This variant is well documented in the literature in individuals with Li-Fraumeni syndrome and various cancers including breast cancer and osteosarcoma (see for example: Stjepanovic. 2018. PubMed ID: 30092803; Wu. 2011. PubMed ID: 21305319; Monti. 2007. PubMed ID: 17606709; Toguchida. 1992. PubMed ID: 1565143; Guindalini. 2022. PubMed ID: 35264596). In vitro experiments have shown the c.743G>A variant results in a dominant-negative allele, and reduces p53 protein activity by ~75% compared to wild-type (Monti. 2011. PubMed ID: 21343334; Zerdoumi. 2017. PubMed ID: 28369373). This variant is reported to segregate with disease within families (Monti. 2007. PubMed ID: 17606709; Wu. 2011. PubMed ID: 21305319), and has been reported to arise as a de novo mosaic germline variant that was later found to be homozygous in numerous tumor samples (Behjati. 2014. PubMed ID: 24810334). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 Variant Curation Expert Panel (VCEP; https://erepo.clinicalgenome.org/evrepo/ui/interpretation/cf887752-8539-4177-a74d-dc5c8f8a36ed), and is classified as pathogenic and likely pathogenic by many other labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12356/). We interpret this variant 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 | - - |
Sarcoma Pathogenic:1
| Pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
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
Pathogenic
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
Uncertain
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;T;D;D;D;D;.
Polyphen
D;.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D
Vest4
MVP
MPC
0.41
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