17-7674230-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS3PS4PP4_ModeratePM1PS2_ModeratePP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.733G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by serine at amino acid 245 (p.Gly245Ser). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; Internal lab contributor: SCV000184981.8). This variant has been reported in an additional individual meeting Classical criteria and 11 individuals meeting Revised Chompret criteria. Based on this evidence, this variant scores 8 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs: 11370630, 32156018, 32888145, 33245408, 34670578, 35974385, 20522432, 24122735, Internal lab contributor: SCV000184981.8). 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: SCV000184981.8). This variant has an allele frequency of 0.000002543 (3/1179926 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 = 0.5536; Align GVGD = Class C55) 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_Moderate, PS4_Very Strong, PP4_Moderate, PM2_Supporting, PS3, PM1, PP3. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000367/MONDO:0018875/009
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.733G>A | p.Gly245Ser | missense_variant | 7/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.733G>A | p.Gly245Ser | missense_variant | 7/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151942Hom.: 0 Cov.: 30
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461784Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727194
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151942Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74230
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 04, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 245 of the TP53 protein (p.Gly245Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Li-Fraumeni syndrome (LFS) or LFS-like syndrome and LFS-related cancers (PMID: 1565143, 11370630, 15925506, 16401470, 17311302, 20522432, 21761402, 24122735, 26225655, 27621308). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12365). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) expected to disrupt TP53 protein function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 12917626, 15722483, 20128691, 21343334, 26205489). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Apr 06, 2023 | The TP53 c.733G>A (p.Gly245Ser) missense change has a maximum subpopulation frequency of 0.0040% in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). This variant has been reported in individuals with LFS-associated cancers (PMID: 11370630, 24122735, 20522432, 12885464). Computational evidence supports a deleterious effect of this variant on protein function and transactivation assays show a low functioning allele according to Kato et al., and evidence of loss of function and a dominant negative effect according to Giacomelli et al. (PMID 12826609, 30224644). This variant is a somatic hotspot variant in tumors. In summary, this variant meets criteria to be classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 24, 2021 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 29, 2016 | - - |
Li-Fraumeni syndrome Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 16, 2016 | The p.Gly245Ser variant in TP53 has been reported in >15 individuals with TP53-a ssociated cancers. It also segregated with disease in at least 8 affected relati ves from multiple families (Varley 1997; Trkova 2003). This variant has also bee n identified in 1/66734 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs29834575). In vitro functional s tudies demonstrate that the p.Gly245Ser variant has a dominant negative effect ( Marutani 1999). In summary, this variant meets criteria to be classified as path ogenic for Li-Fraumeni syndrome in an autosomal dominant manner based upon segre gation studies, low frequency in controls, and functional evidence. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 27, 2023 | Variant summary: TP53 c.733G>A (p.Gly245Ser) 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 was absent in 251472 control chromosomes. c.733G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome, osteosarcoma and other cancers (examples: Toguchida_1992, Giacomazzi_2013, Melhem-Bertrandt_2012, Bougeard_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired DNA binding, transcriptional activation, and growth suppression activities, with a dominant-negative effect observed (Monti_2011, Kato_2003, etc). 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories, including an expert panel, classified 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 | Invitae | Jan 05, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 245 of the TP53 protein (p.Gly245Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Li-Fraumeni syndrome (LFS) or LFS-like syndrome and LFS-related cancers (PMID: 1565143, 11370630, 15925506, 16401470, 17311302, 20522432, 21761402, 24122735, 26225655, 27621308). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12365). 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, 12917626, 15722483, 20128691, 21343334, 26205489). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen TP53 Variant Curation Expert Panel, ClinGen | Aug 28, 2019 | This variant is within a codon that is an established hotspot in the TP53 gene (PM1; PMID: 2046748). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in at least 3 probands meeting classic Li-Fraumeni syndrome criteria and at least 2 probands meeting Chompret criteria (PS4; PMID: 11370630, 24122735, 20522432, 12885464). In summary, TP53 c.733G>A; p.Gly245Ser meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PP3, PS3, PS4. - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 27, 2022 | PP3, PP5, PM1, PM2, PS3, PS4 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Dec 03, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2021 | Published functional studies demonstrate a damaging effect: impaired DNA binding, transcriptional activation, and growth suppression activities, with a dominant-negative effect observed (Kato 2003, Malcikova 2010, Monti 2011, Kotler 2018); Not observed at 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: 23334668, 16401470, 27045317, 28222664, 30592087, 31081129, 20128691, 17606709, 21665182, 19367569, 1565143, 24573247, 25637381, 21343334, 25503501, 24122735, 26822949, 21761402, 17311302, 12676907, 26786923, 26641009, 24835218, 26225655, 27621308, 28369373, 28573494, 29602769, 28724667, 29025599, 29338689, 29979965, 28472496, 28975465, 23538418, 30076369, 29093764, 30720243, 30322717, 30093976, 30840781, 29263802, 30816478, 15951970, 31105275, 32000721, 27535533, 15510160, 29351919, 28929227, 32475984, 32156018, 33300245) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 12, 2013 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 18, 2023 | This missense variant replaces glycine with serine at codon 245 in the DNA binding domain 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 transactivation assays (PMID: 11370630, 12826609, 15781620) and in cell growth assays (PMID: 29979965, 30224644). This variant has been reported in multiple individuals affected with either classic Li-Fraumeni syndrome (PMID: 11370630, 12885464 32156018, 32817165, 33163847, 33840814, 34709361, 35974385) or meeting the Chompret criteria for Li-Fraumeni syndrome, including individuals with early-onset breast cancer (PMID:20522432, 32888145, 32888145, 33245408, 34529667, 359743855; Color Health internal data). 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 Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 07, 2024 | The p.G245S pathogenic mutation (also known as c.733G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 733. The glycine at codon 245 is replaced by serine, an amino acid with similar properties. This variant has been reported in multiple individuals with clinical and family histories consistent with Li-Fraumeni syndrome (Toguchida J et al. N. Engl. J. Med. 1992 May;326:1301-8; Bougeard G et al. J Med Genet, 2001 Apr;38:253-7; Trkova M et al. Cancer Genet Cytogenet, 2003 Aug;145:60-4; Wong P et al. Gastroenterology. 2006 Jan;130:73-9; Ruijs MW et al. J Med Genet, 2010 Jun;47:421-8; Giacomazzi J et al. Cancer. 2013 Dec;119:4341-9). This variant has been determined to be the result of a de novo mutation or germline mosaicism in in one child with a choroid plexus carcinoma (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 (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 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 been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). 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. - |
Ovarian neoplasm Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | University Health Network, Princess Margaret Cancer Centre | Mar 19, 2021 | - - |
Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
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 | - - |
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 | - - |
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 | Sep 10, 2021 | - - |
Adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Adrenocortical carcinoma, hereditary Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Colorectal cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | case-control | Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo | - | - - |
Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;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;C4748488:Bone marrow failure syndrome 5 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 16, 2022 | - - |
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 | - - |
Xeroderma pigmentosum Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 27, 2023 | Variant summary: ERCC2 c.733G>A (p.Asp245Asn) results in a conservative amino acid change located in the DEAD2 domain (IPR010614) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250228 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.733G>A in individuals affected with Xeroderma Pigmentosum and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Multiple acyl-CoA dehydrogenase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 27, 2023 | Variant summary: ETFA c.733G>A (p.Val245Ile) results in a conservative amino acid change located in the Electron transfer flavoprotein, alpha subunit, C-terminal domain (IPR014731) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251078 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.733G>A has been reported in the literature in individuals affected with Glutaric Aciduria, Type 2a. These report(s) do not provide unequivocal conclusions about association of the variant with Glutaric Aciduria, Type 2a. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Astrocytoma, anaplastic Pathogenic:1
Pathogenic, no assertion criteria provided | research | Tampere Brain Tumor Research Consortium, University of Tampere | - | - - |
Ovarian serous cystadenocarcinoma 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 | - - |
Atypical teratoid rhabdoid tumor Pathogenic:1
Pathogenic, no assertion criteria provided | research | Tampere Brain Tumor Research Consortium, University of Tampere | - | - - |
Neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Pancreatic adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Li-fraumeni-like syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1995 | - - |
Lung adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Familial ovarian cancer Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The TP53 p.Gly245Ser variant was identified in 8 of 2224 proband chromosomes (frequency: 0.004) from Spanish, Dutch, British, and American individuals or families with Li-Fraumeni syndrome, and Li-Fraumeni syndrome with breast cancer (BRCA1/2 negative and early onset, or with a family history of multiple primary cancers, or HER-2 positive) or early onset CRC, and was not identified in 300 chromosomes from healthy individuals (Llovet 2017 , Martin 2003, Maxwell 2014, Ruijis 2009, Eccles 2016, Wong 2006). The variant falls within 1 of 5 conserved domains for which the majority of disease associated mutations (hotspots) occur (codons 175, 245, 248, 249 and 273); the variant is a structural mutant that is moderately destabilized when compared to wild-type p53 and has partial DNA binding thereby affecting the protein’s transcriptional activity, as evidenced through multiple studies using molecular dynamics simulations, crystallography/NMR Spectroscopy (Martin 2003, Lepre 2017, Wong 1999, Merabet 2010, Joerger 2006).The variant was also identified in dbSNP (ID: rs28934575) “With Likely pathogenic,Pathogenic allele”, ClinVar (classified pathogenic by Ambry Genetics, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), GeneDx, Invitae, Pathway Genetics and OMIM; and likely pathogenic by CSER_CC_NCGL (University of Washington Medical Center)), Clinvitae (1x), Cosmic (in numerous tumour tissue types: brain, breast, liver, lung, pancreatic, bladder, oesophageal, colon, stomach,ovarian, prostate, and uterine), UMD TP53 Mutation Database, and Database of germline p53 mutations. The variant was not identified in Genesight-COGR, LOVD 3.0, and IARC TP53 Database. The variant was identified in control databases in 1 of 277132 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017), seen in the African population in 1 of 23998 chromosomes (freq: 0.00004), while not observed in the Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Gly245 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Ser variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
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, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 06, 2023 | The TP53 c.733G>A variant is predicted to result in the amino acid substitution p.Gly245Ser. This variant has been identified in individuals with a personal or family history of Li-Fraumeni syndrome and related cancers (Toguchida. 1992. PubMed ID: 1565143; Wong. 2006. PubMed ID: 16401470; Melhem-Bertrandt. 2012. PubMed ID: 21761402; Giacomazzi. 2013. PubMed ID: 24122735; Table S4, Bhai. 2021. PubMed ID: 34326862; Table S2, Guindalini. 2022. PubMed ID: 35264596). Functional analysis showed that this variant resulted in severe deficiency of transactivation activity and TP53 functionality (Table S1, Monti. 2011. PubMed ID: 21343334; Table 1, Zerdoumi. 2017. PubMed ID: 28472496). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and has been reported in ClinVar by multiple sources as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12365/). 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 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at