chr17-7673772-C-T

Position:

chr17-7673772-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PM5PP3BS2

The NM_000546.6(TP53):c.848G>A(p.Arg283His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,966 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R283C) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 3.18

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:

TP53 (HGNC:):

TP53 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 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

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7673773-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.746

BS2

High AC in GnomAdExome4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.848G>A	p.Arg283His	missense_variant	8/11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.848G>A	p.Arg283His	missense_variant	8/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251452

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 10, 2024	This missense variant replaces arginine with histidine at codon 283 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies assessing transcriptional transactivation activity have demonstrated partial impact to normal function (PMID: 9525742, 9546439, 9627118, 11429700, 11429705, 12826609, 16861262, 17311302, 21343334). However, studies of human cell proliferation and growth suppression showed no loss of TP53 function (PMID: 29979965, 30224644). This variant has been reported in individuals affected with breast cancer and astrocytoma in the literature (PMID: 10557074, 12019170, 26681312; DOI: 10.21203/rs.3.rs-1200021/v2). This variant has been identified in 10/251452 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 283 of the TP53 protein (p.Arg283His). This variant is present in population databases (rs371409680, gnomAD 0.01%). This missense change has been observed in individual(s) with astrocytoma and glioblastoma (PMID: 10557074, 12019170). ClinVar contains an entry for this variant (Variation ID: 142324). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 9525742, 9546439, 9627118, 11429705, 12019170, 12826609, 16861262, 17311302, 21343334, 29979965, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Li-Fraumeni syndrome 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 21, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 06, 2020	The TP53 c.848G>A; p.Arg283His variant (rs371409680), is reported in the literature in individuals affected with an astrocytoma or a glioblastoma (Fulci 2002, Ishii 1999) and in an individual with breast cancer (Susswein 2016). This variant is reported as likely pathogenic/uncertain significance by multiple laboratories in ClinVar (Variation ID: 142324), and is found in the general population with an overall allele frequency of 0.004% (10/ 251,452 alleles) in the Genome Aggregation Database. The arginine at codon 283 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show variable results, although many show decreased transactivation and a moderate dominant-negative effect (see link TP53MutLoad database, Campomenosi 2001, Crook 1998, Di Como 1998, Flaman 1998, Fulci 2002). Additionally, recent analyses of Genome Aggregation Database frequency compared to affected individuals do not reach a consensus as to the clinical significance (Evans 2019, Fortuno 2019, Soussi 2019). Therefore, due to conflicting results, the clinical significance of this variant is uncertain. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2025	Published functional studies are conflicting: this variant is reported to have non-functional transactivation; however, p53 response elements other than the BAX reporter have been normal or partially present, apoptotic activity was not impacted, and colony formation and growth suppression assays were similar to wild type (PMID: 9525742, 9627118, 9546439, 10753186, 11429705, 11238924, 11429700, 12019170, 11896595, 12909720, 16861262, 21343334, 29979965, 30224644, 12826609); Identified in individuals with breast, brain, or other cancers, with none to date reported as meeting Li-Fraumeni diagnostic criteria (PMID: 10557074, 30128536, 35451682, 39007733); 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, 12909720, 11429700, 29979965, 17606709, 21343334, 30577483, 28861920, 30128536, 29922827, 30851333, 12019170, 9525742, 21674059, 11238924, 10753186, 11429705, 11896595, 16861262, 9546439, 26681312, 10229196, 28915717, 29301828, 28418444, 28218421, 9627118, 30352134, 30720243, 30840781, 31016814, 33257846, 30224644, 17311302, 32164171, 32722340, 32966936, 31105275, 31620276, 16000567, 12917626, 9572492, 35451682, 35490794, 10557074, 15173255, 24729566, 25460562, 35033608, 36353970, 18628487, 26743472, 15580553, 11715068, 11358831, Fu2022, 12826609, 36243179, 35150601, 39007733, 15510160) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 11, 2023	The p.R283H variant (also known as c.848G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 848. The arginine at codon 283 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in a 41 year-old male with astrocytoma (Fulci G et al. Cancer Res. 2002 May;62:2897-905). This alteration has been identified in one family with a history consistent with Li-Fraumeni-like syndrome; however, this alteration has also been detected numerous times in our laboratory in individuals with a personal and family history inconsistent with a diagnosis of Li Fraumeni syndrome (Ambry internal data). Transactivation studies conducted in yeast and mammalian cells have shown variable results, with the altered protein able to activate some, but not all, downstream targets (Fulci G et al. Cancer Res. 2002 May;62:2897-905; Campomenosi P et al. Oncogene. 2001 Jun;20:3573-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9; Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98; Crook T et al. Oncogene. 1998 Mar;16:1429-41; IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul;100:8424-9). This variant also has conflicting reports of intracellular localization, with one group showing nuclear localization in yeast (Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98), and another showing nuclear exclusion in a human lymphoma cell line (Crook T et al. Oncogene. 1998 Mar;16:1429-41). However, this alteration has been shown to be proficient at growth suppression in multiple mammalian cell lines (Crook T et al. Oncogene. 1998 Mar;16:1429-41; Fulci G et al. Cancer Res. 2002 May;62:2897-905; Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear, and we cannot rule out the possibility that it is a low penetrance risk allele. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 30, 2023	This missense variant replaces arginine with histidine at codon 283 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). Experimental functional studies assessing transcriptional transactivation activity have demonstrated partial impact to normal function (PMID: 9525742, 9546439, 9627118, 11429700, 11429705, 12826609, 16861262, 17311302, 21343334). However, studies of human cell proliferation and growth suppression showed no loss of TP53 function (PMID: 29979965, 30224644). This variant has been reported in individuals affected with breast cancer and astrocytoma in the literature (PMID: 10557074, 12019170, 26681312; DOI: 10.21203/rs.3.rs-1200021/v2). This variant has been identified in 10/251452 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 19, 2020

DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.848G>A, in exon 8 that results in an amino acid change, p.Arg283His. This sequence change has been reported in the gnomAD databases with an overall frequency of 0.004% and 0.01% in the South Asian population (dbSNP rs371409680). The p.Arg283His has been described in an individual with TP53-related astrocytoma and glioblastoma (PMID: 12019170) and an individual with breast cancer (PMID: 26681312). Functional studies have demonstrated that this variant may affect TP53 transactivation activity to varying degrees, with some demonstrating retention of near-wild-type protein function (PMID: 21343334, 12019170, 12826609, 9627118, 16861262, 9546439, 11429705). One study revealed that this variant leads to mislocalization of the TP53 protein, but retained some growth suppressive and apoptotic activity (PMID: 9525742). The p.Arg283His change affects a moderately conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg283His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). Due to the conflicting functional studies and the presence of this variant in the population databases, the clinical significance of the p.Arg283His change remains unknown at this time. -

Adrenocortical carcinoma, hereditary

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 17, 2023

- -

Astrocytoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 16, 2016

Identified by sequencing as part of the NHLBI Sequencing Project (ESP; no phenotype data). Reported in a patient with astroctyoma (PMID 12019170). Identified in a 14 year old with adrenocortical carcinoma inherited from an unaffected father and in a 32 year old woman with a history of cardiac paraganglioma and maternal family history of breast cancer (personal communication with Chimene Kesserwan and Arielle Yorczyk-Swanholm). -

TP53-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2023

The TP53 c.848G>A variant is predicted to result in the amino acid substitution p.Arg283His. This variant was reported in individuals with astrocytoma, glioblastoma, or breast cancer (Fulchi et al. 2002. PubMed ID: 12019170; Table S1, Susswein et al. 2016. PubMed ID: 26681312; Table S4, Rana et al. 2019. PubMed ID: 31105275). However, this variant was also documented in individuals unselected for cancer testing (Table S1, de Andrade et al. 2017. PubMed ID: 28861920; Evans et al. 2019. PubMed ID: 31016814). Functional studies in different laboratories showed variable and even contradictory results regarding the transactivation activity and subcellular localization (Crook et al. 1998. PubMed ID: 9525742; Dearth et al. 2006. PubMed ID: 16861262; Table S1, Monti et al. 2007. PubMed ID: 17606709; Tables S1 and S3, Monti et al. 2011. PubMed ID: 21343334). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7577090-C-T) and is interpreted as a variant of uncertain significance by most of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142324/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

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

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.78

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.75

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

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

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.1

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

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0050

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

Polyphen

0.95, 0.93, 1.0

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

Vest4

0.77

MVP

0.97

MPC

0.40

ClinPred

0.68

GERP RS

4.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.80

gMVP

0.29

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