17-7675088-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP1_ModeratePP3PM1PS4_ModeratePS3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.524G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 175 (p.Arg175His). This variant has been reported in 3 unrelated families meeting Classic and Revised Chompret criteria.Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate: 8825920, 11370630, 8164043). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in 1 family (PP1_Moderate; PMID:8825920). 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 (PS3; PMIDs: 12826609, 30224644, 29979965). 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 (PM1; PMID:8023157). Computational predictor scores (BayesDel = 0.54619; Align GVGD = Class C25) 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). This variant has an allele frequency of 0.000005932 (7/1180032 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 summary, this variant meets the criteria to be classified as [CLASSIFICATION] for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP1_Moderate, PM1, PS4_Moderate, PP3, PM2_Supporting. (Bayesian Points: 12; VCEP specifications version 2.0; 9/6/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000251/MONDO:0018875/009

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:36O:1

Conservation

PhyloP100: 6.16

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 12 ACMG points.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.524G>A	p.Arg175His	missense_variant	Exon 5 of 11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.524G>A	p.Arg175His	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

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:

251276

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135832

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727234

show subpopulations

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

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:

0.0000297

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:36Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Apr 17, 2017

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato et al., 2003; Monti et al., 2011; Wasserman et al., 2015; 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: 31447099, 31105275, 15510160, 12826609, 19556618, 21343334, 25584008, 29979965, 8118819, 8164043, 10864200, 12200603, 16401470, 22233476, 28369373, 30577483, 30840781, 30093976, 29324801, 30092803, 30720243, 30709875, 28472496, 29753700, 29360550, 28975465, 29470806, 19127115, 29360161, 28818432, 29416795, 27153395, 12610779, 11494139, 11370630, 8308926, 7887414, 8099841, 23792586, 20689556, 15492269, 21426305, 22006311, 24573247, 22286061, 21305319, 17606709, 21761402, 24651015, 20128691, 24729566, 15170137, 29489754, 28861920, 28724667, 15607981, 15607980, 27516001, 27374712, 27714481, 27501770, 27323394, 23172776, 22265402, 21601526, 22851211, 21059199, 20501846, 18511570, 17308077, 16551709, 15951970) -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Li-Fraumeni syndrome 1

Pathogenic:8

Jun 18, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 11, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:8825920, 8118819, 7887414]. Functional studies indicate this variant impacts protein function [PMID: 14743206, 15607980]. This variant is expected to disrupt protein structure [PMID: 8023157, Myriad internal data]. -

Mar 18, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 24, 2014

Pathway Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TP53 p.Arg175His variant was identified in 14 of 2378 proband chromosomes (frequency: 0.006) from individuals or families with Li Fraumeni syndrome, breast, ovarian and/or colon cancer (Walsh 2011, Melhem-Bertrandt 2012, Wong 2006, Bougeard 2008, Damineni 2014). This variant has also been identified in a child diagnosed with adrenocortical carcinoma at 6 months of age (Choong 2012) and a family that includes two individuals diagnosed with childhood sarcomas and four individuals diagnosed with brain tumours (Varley 1995). The variant was identified in dbSNP and ClinVar (classified as pathogenic by GeneDx, Invitae, Ambry Genetics, and 8 other submitters) . The variant was identified in control databases in 1 of 251276 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 1 of 113600 chromosomes (freq: 0.000009), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The R175 residue is a mutation hotspot and results in a structurally unstable, unfolded p53 protein (Xu 2014). The R175H variant has been shown to confer oncogenic gain of function to the p53 protein by multiple studies (Petitjean 2007, Capponcelli 2005), which is hypothesized to occur via the increased activation of the c-Met receptor tyrosine kinase and/or the inactivation of the ATM-dependent DNA damage response, resulting in a defective G2/M checkpoint (Grugan 2013, Liu 2010). The p.Arg175 residue is conserved across mammals and other organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the His 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Dec 15, 2020

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 12, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PS4,PM1,PP3 -

Li-Fraumeni syndrome

Pathogenic:6

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 175 of the TP53 protein (p.Arg175His). This variant is present in population databases (rs28934578, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 8164043, 8825920, 16401470, 21761402, 22006311). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12374). Invitae Evidence Modeling incorporating data from in vitro 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: 12007217, 12826609, 15607980, 15607981, 20516128, 23263379, 24573247, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. -

Sep 06, 2024

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6: c.524G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 175 (p.Arg175His). This variant has been reported in 3 unrelated families meeting Classic and Revised Chompret criteria.Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate: 8825920, 11370630, 8164043). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in 1 family (PP1_Moderate; PMID: 8825920). 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 (PS3; PMIDs: 12826609, 30224644, 29979965). 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 (PM1; PMID: 8023157). Computational predictor scores (BayesDel = 0.54619; Align GVGD = Class C25) 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). This variant has an allele frequency of 0.000005932 (7/1180032 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 summary, this variant meets the criteria to be classified as [CLASSIFICATION] for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP1_Moderate, PM1, PS4_Moderate, PP3, PM2_Supporting. (Bayesian Points: 12; VCEP specifications version 2.0; 9/6/2024) -

Sep 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 175 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 that this variant results in the loss of TP53 protein function (PMID: 12826609, 15607981, 23263379, 29979965, 30224644), causes chromosomal instability (PMID: 25059482), and promotes tumor cell invasion (PMID: 15607981, 23792586). In mouse models of Li-Fraumeni syndrome, this variant has also been shown to impair TP53 function and cause TP53-related tumors (PMID: 15607980, 15607981). This variant has been reported in individuals affected with Li-Fraumeni syndrome meeting classic or Chompret diagnostic criteria (PMID: 8164043 , 8825920, 16401470, 21761402, 23172776, 27374712, 27516001). This variant has been shown to segregate with disease in a 4-generation extended family affected with Li-Fraumeni syndrome (PMID: 8825920). This variant has been identified in 1/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Jan 10, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The following ACMG criteria was used: PS3, PP1_MOD, PM1, PS4_MOD, PP3, PM2_SUP -

Jul 24, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg175His variant in TP53 has been reported in >16 individuals with Li-Fra umeni syndrome, and segregated with disease in 3 affected relatives from 1 famil y (McIntyre 1994, Varley 1997, Wong 2006, Bougeard 2008, Walsh 2011, Melhem-Bert randt 2012, Park 2016). This variant has also been reported by another clinical laboratory in ClinVar (Variation ID# 12374). In vitro functional studies provide some evidence that the p.Arg175His variant may impact protein function (Kogan-S akin 2011, Grugan 2013) and an in-vivo mouse model has shown that this variant c auses TP53-related tumors (Liu 2010). Additionally, the p.Arg175His variant has been identified in 1/111550 European chromosomes by gnomAD (http://gnomad.broadi nstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg175His variant may impact the protein and 3 other amino acid chang es at this position (Leu, Gly, Cys) have been associated with Li-Fraumeni syndro me (HGMD database; Stenson 2017). In summary, this variant meets criteria to be classified as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manne r based on segregation studies, increased prevalence in affected individuals, ve ry low frequency in controls and functional evidence. ACMG/AMP Criteria applied: PS4, PP1, PS3, PM2. -

Jan 07, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TP53 c.524G>A (p.Arg175His) results in a non-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 4e-06 in 251276 control chromosomes. c.524G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome, including 2 families where the variant strongly segregated with disease (Varley_1995, Varley_1997, etc). These data indicate that the variant is very likely to be associated with disease. In vitro functional studies show that R175H results in decreased activation of Tp53 targets, and additionally confers a gain of function to Tp53, resulting in aberrant activation of gene transcription and enhanced cell migration (TP53 database, Yeudall_2012). Additional evidence from an animal model indicates that this variant contributes to a phenotype similar to tumorigenesis (including thymic tumors, sarcomas, peripheral lymphomas and germ-cell tumors) (Liu_2010). Ten ClinVar submitters have assessed this variant since 2014: all ten classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:4

Sep 19, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R175H pathogenic mutation (also known as c.524G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 524. This changes the amino acid from an arginine to a histidine at codon 175. This mutation occurs at a well-characterized mutation hotspot (codon 175) in the critical DNA binding domain, and is associated with a classic LFS-associated tumor spectrum, including osteosarcomas, rhabdomyosarcomas, early onset colon cancer, breast cancer, and pediatric adrenal cortical tumors (McIntyre JF et al. J. Clin. Oncol. 1994 May;12(5):925-930; Varley JM et al. J. Med. Genet. 1995 Dec;32:942-945; Wong P et al. Gastroenterology. 2006 Jan;130:73-79; Hwang SM et al. Korean J. Lab Med. 2008 Dec;28(6):493-497; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118(4):908-13; Choong SS et al. Clin. Genet. 2012 Dec;82(6):564-8; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Park KJ et al. Ann. Lab. Med. 2016 Sep;36:463-8; Dudley B et al. Cancer. 2018 Apr;124(8):1691-1700). This variant 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 observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Dec 09, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant NM_000546.6(TP53):c.524G>A (p.Arg175His) causes the same amino acid change as a previously established pathogenic variant. There is a small physicochemical difference between arginine and histidine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene TP53 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.15. The p.Arg175His missense variant is predicted to be damaging by both SIFT and PolyPhen2. . The nucleotide c.524 in TP53 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic -

Jun 18, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Malignant tumor of esophagus

Pathogenic:1

Jul 29, 2016

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

SIFT:Deleterious (score: 0) MutationTaster:Disease causing (p-value: 1) -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial cancer of breast

Pathogenic:1

Mar 19, 2021

University Health Network, Princess Margaret Cancer Centre

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ovarian neoplasm

Pathogenic:1

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Lip and oral cavity carcinoma

Pathogenic:1

Apr 30, 2019

Institute of Medical Sciences, Banaras Hindu University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Adrenocortical carcinoma, hereditary

Pathogenic:1

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer

Pathogenic:1

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

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

Apr 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TP53-related disorder

Pathogenic:1

May 01, 2024

Swedish National ChiCaP Initative, Genomic Medicine Sweden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Squamous cell carcinoma of the head and neck

Pathogenic:1

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

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

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.86

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

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.6

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

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.8

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

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

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

Polyphen

1.0

D;.;.;.;.;.;.;.;.;P;.;P;D;P;.;.;P;.;.;.;D

Vest4

0.94

MutPred

0.99

Loss of stability (P = 0.0011);Loss of stability (P = 0.0011);.;.;.;.;.;.;.;Loss of stability (P = 0.0011);.;Loss of stability (P = 0.0011);Loss of stability (P = 0.0011);Loss of stability (P = 0.0011);.;.;Loss of stability (P = 0.0011);.;.;.;.;

MVP

1.0

MPC

1.1

ClinPred

0.99

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

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