chr17-7673776-G-A

Position:

chr17-7673776-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000546.6(TP53):c.844C>T(p.Arg282Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:51B:1O:1

Conservation

PhyloP100: 4.02

Variant links:

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]

TP53 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7673775-C-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

PP5

Variant 17-7673776-G-A is Pathogenic according to our data. Variant chr17-7673776-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7673776-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-7673776-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.844C>T	p.Arg282Trp	missense_variant	8/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.844C>T	p.Arg282Trp	missense_variant	8/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251410

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727232

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152016

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000659

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:51Benign:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1

Pathogenic:11

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The TP53 c.844C>T (p.Arg282Trp) variant is listed as a common somatic and germline variant in the IARC TP53 variant database (Arcand et al. 2015; Wassermann et al. 2015). Across a selection of the available literature the TP53 c.844C>T (p.Arg282Trp) variant has been identified in at least nine individuals with different types of cancer, all in a heterozygous state (Toguchida et al. 1992; Malkin et al. 1992; Audrezet et al. 1996; Prochazkova et al. 2009; Pinto et al. 2009; Melhem-Bertrandt et al. 2012; Sokolenko et al. 2015). The p.Arg282Trp variant has also been found in a heterozygous state in at least two asymptomatic family members. The variant was absent from 200 control individuals and is reported at a frequency of 0.0002 in the European American population of the Exome Sequencing Project. This frequency is based on two alleles in a region of good coverage so the variant is presumed to be rare. Functional studies using the p.Arg282Trp variant protein document that the variant destabilizes the protein, increases aggregation and alters signalling to increase cellular invasion (Zhang et al. 2016). Based on the collective evidence, the p.Arg282Trp variant is classified as pathogenic for Li-Fraumeni syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Nov 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R282W in TP53 (NM_000546.6) has been reported in multiple affected patients (Mannan AU et al; Siraj AK et al). Functional studies suggest a damaging effect (Zerdoumi Y et al). The variant has been submitted to ClinVar as Pathogenic. The p.R282W variant is observed in 1/1,13,728 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R282W missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 282 of TP53 is conserved in all mammalian species. The nucleotide c.844 in TP53 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 06, 2021	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	This sequence change replaces Arginine with Tryptophan at codon 282 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein which interacts with multiple proteins. This variant is present in population databases at a very low frequency ( rs28934574, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 25584008, 21305319, 21761402, 1565143). 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. In addition, experimental studies have shown that this variant affects TP53 transactivation activity at variable levels. The mutation database ClinVar contains entries for this variant (Variation ID:12364). Therefore, this variant is considered as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Personalized Medicine, Children's Hospital Los Angeles	Feb 04, 2018	- -
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: 1565144, 8425176, 16206219, 22672556, 33407742, 29581140]. Functional studies indicate this variant impacts protein function [PMID: 1631137, 17015838, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary cancer-predisposing syndrome

Pathogenic:7

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Oct 31, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
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	Ambry Genetics	Jun 29, 2021	The p.R282W pathogenic mutation (also known as c.844C>T), located in coding exon 7 of the TP53 gene, results from a C to T substitution at nucleotide position 844. The arginine at codon 282 is replaced by tryptophan, an amino acid with dissimilar properties. This pathogenic mutation has been reported in multiple individuals or families with Li-Fraumeni Syndrome (LFS) or LFS-like syndrome (Toguchida J et al. N. Eng. J. Med. 1992 May;326(20):1301-8; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118(4):908-13; Kast K et al. BMC Cancer. 2012 Jun;12:217; Mannan AU et al. J. Hum. Genet. 2016 Jun;61:515-22; Siraj AK et al. Hum. Genet. 2017 11;136:1431-1444). In an analysis of data from the p53 germline mutation database, mutations at position R282 were shown to have an association with early onset bone cancers (Xu J et al. Sci. Rep. 2014;4:4223). 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). Based on the available evidence, this alteration is classified as a pathogenic mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2022	This missense variant replaces arginine with tryptophan at codon 282 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 that this variant causes reduced transactivation activity, dominant negative effect, and loss of function in human cell proliferation and growth suppression assays (PMID: 12826609, 15958617, 21343334, 29979965, 30224644). This variant has been reported in many individuals affected with breast cancer, Li-Fraumeni syndrome, and Li-Fraumeni-like syndrome meeting Chompret criteria, including several de novo cases (PMID: 8402598, 8425176, 11370630, 1565143, 16206219, 19468865, 21305319, 21761402, 22672556, 25584008, 25619955, 28975465, 30709381). This variant has been identified in 1/251410 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	GeneKor MSA	Jan 01, 2020	This sequence change replaces Arginine with Tryptophan at codon 282 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein which interacts with multiple proteins. There is a large physiochemical difference between arginine and tryptophan (Grantham Score 101).This variant is present in population databases at a very low frequency ( rs28934574, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 25584008, 21305319, 21761402, 1565143). 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. In addition, experimental studies have shown that this variant affects TP53 transactivation activity at variable levels. In summary, this is a rare sequence change that is expected to affect the TP53 protein and cause disease.The mutation database Clinvar contains entries for this variant (Variation ID:12364). -

Li-Fraumeni syndrome

Pathogenic:4Benign:1

Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 282 of the TP53 protein (p.Arg282Trp). This variant is present in population databases (rs28934574, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (LFS) or Li-Fraumeni-like syndrome (PMID: 1565143, 1565144, 11370630, 21305319, 21761402, 25584008). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12364). 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, 29979965, 30224644). 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 03, 2022	The p.Arg282Trp variant in TP53 has been reported in at least 4 individuals with features of Li-Fraumeni syndrome (Wasseman 2015 PMID: 25584008, Wu 2011 PMID: 21305319, Melhem-Bertrandt 2012 PMID: 21761402,Toguchida 1992 PMID: 1565143) and in ClinVar (Variation ID 12364). It has also been identified in 1/68022 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg282Trp variant is located in the DNA binding domain of the TP53 protein and in vitro functional assays support impact on protein function with loss of transactivation capacity and dominant negative effect, affecting several p53 isoforms (IARC TP53 database, Monti 2011 PMID: 21343334, Zerdoumi 2017 PMID: 28472496, Kato 2003 PMID: 12826609). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP criteria applied: PM1, PP3, PS3, PS4, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2023	Variant summary: TP53 c.844C>T (p.Arg282Trp) 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 251810 control chromosomes. c.844C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome. Experimental studies have shown the variant to have a damaging effect on protein function. The following publications have been ascertained in the context of this evaluation (PMID: 23246812, 11370630, 27895058, 16818505, 11782540, 22915647, 21059199, 26230955, 1349175, 21519010, 20407015, 27463065, 22672556, 1565144, 30327374, 17606709, 21343334, 26585234, 25952993, 27276561, 22186996, 27680515, 1565143, 27959731, 21305319, 24857548). 21 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters 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	Mendelics	Jul 02, 2018	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2021	Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato et al., 2003; Scian et al., 2004; 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: 32658383, 32475984, 31980526, 31105275, 32098966, 31537539, 31081129, 31159747, 30840781, 31016814, 30720243, 30709381, 28472496, 25186627, 28975465, 29555771, 29752822, 28861920, 29581140, 15280671, 29979965, 29315962, 29506128, 29300620, 29237527, 27882657, 28534505, 27683180, 28091804, 28369373, 27680515, 28387325, 28527674, 27077130, 28397142, 25925845, 8402598, 19468865, 18669439, 1349175, 8425176, 10864200, 21761402, 22672556, 27501770, 27714481, 27619989, 26911350, 25385265, 26878390, 26014290, 25619955, 15077194, 21343334, 21305319, 25637381, 24651015, 24573247, 14583457, 16206219, 1565144, 25584008, 19012332, 11370630, 21059199, 1565143, 12517413, 21445056, 12917626, 12826609, 16861262, 1631137, 17606709) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 08, 2018	DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.844C>T, in exon 8 that results in an amino acid change, p.Arg282Trp. The p.Arg282Trp change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg282Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been described in the EXAC database with a low population frequency of 0.002% (dbSNP rs28934574). The p.Arg282Trp pathogenic sequence change has previously been described in multiple unrelated individuals with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome, and has been observed in the de novo state in at least two affected individuals (Malkin et al., 1992; Bougeard et al., 2001; Pinto et al., 2009; Wu et al., 2011; Kast et al., 2012; Melhem-Bertrandt et al., 2012; Wasserman et al., 2015). Functional studies have provided evidence that the p.Arg282Trp sequence change has a dominant negative effect and leads to significantly reduced TP53 transcriptional activity in response to DNA damage (Zerdoumi et al., 2017). -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Squamous cell carcinoma of the head and neck

Pathogenic:2

Pathogenic, criteria provided, single submitter	case-control	Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo	-	- -
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

- -

Breast neoplasm

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

- -

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

- -

Adrenocortical carcinoma, hereditary

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 14, 2024

- -

Colorectal cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

case-control

Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo

- -

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

- -

Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital

Feb 12, 2019

- -

Papillary renal cell carcinoma type 1

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

- -

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

- -

Li-fraumeni-like syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1995

- -

Non-Hodgkin lymphoma

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

- -

Astrocytoma, anaplastic;C0334586:Pleomorphic xanthoastrocytoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Nov 04, 2016

This is a missense alteration in which a C is replaced by a T at coding nucleotide 844 and is predicted to change an Arginine to a Tryptophan at amino acid codon 282. Classification criteria: PS3, PM1, PM2, PP3, PP5. -

Neoplasm

Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.

Eigen

Uncertain

0.40

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.1

.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.4

D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0020

D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.

Vest4

0.91

MVP

0.98

MPC

0.39

ClinPred

1.0

GERP RS

1.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.91

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over