17-7673776-G-A

Variant names:

• chr17-7673776-G-A
• rs28934574
• NM_000546.6:c.844C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000407070: 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)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282Q) has been classified as Uncertain significance.

• 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:36 B:1 O:11
• Conservation: PhyloP100: 4.02
• Publications: 1096 publications found

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 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000407070: 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).; SCV002073337: Functional studies suggest a damaging effect (Zerdoumi Y et al).; SCV004015238: Experimental studies have shown that this variant affects TP53 transactivation activity at variable levels. PMID:25584008, 21305319, 21761402, 1565143; SCV004017907: Functional studies indicate this variant impacts protein function [PMID: 1631137, 17015838, 29979965].; SCV000253852: Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 29979965, 30224644).; SCV004241252: Experimental studies have shown the variant to have a damaging effect on protein function. 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; SCV004848861: "In vitro functional assays support impact on protein function with loss of transactivation capacity and dominant negative effect, affecting several p53 isoforms." PMID:21343334, PMID:28472496, PMID:12826609; SCV005425720: 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).; SCV000581079: 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).; SCV000691656: Functional studies have shown that this variant is deficient for transcriptional transactivation activity, causes a dominant negative effect, and exhibits loss of function in human cell proliferation and growth suppression assays (PMID: 12826609, 15958617, 21343334, 29979965, 30224644).; SCV000821787: Experimental studies have shown that this variant affects TP53 transactivation activity at variable levels. PMID:25584008, 21305319, 21761402, 1565143; SCV005407751: Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3).; SCV000292698: 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); SCV002069228: 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).
• PM1: In a hotspot region, there are 52 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 24 uncertain 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-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 376659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 12364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.844C>T	p.Arg282Trp	missense	Exon 8 of 11	NP_000537.3
	TP53	NM_001126112.3		c.844C>T	p.Arg282Trp	missense	Exon 8 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.844C>T	p.Arg282Trp	missense	Exon 9 of 12	NP_001394191.1	K7PPA8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.844C>T	p.Arg282Trp	missense	Exon 8 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.844C>T	p.Arg282Trp	missense	Exon 8 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.727C>T	p.Arg243Trp	missense	Exon 7 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152016 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251410 AF XY: 0.00

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 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: 0 AN: 1461868 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152016 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74232

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000276 Hom.: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Li-Fraumeni syndrome 1 (11)
8	-	-	Hereditary cancer-predisposing syndrome (8)
5	-	1	Li-Fraumeni syndrome (6)
4	-	-	not provided (4)
1	-	-	Adrenocortical carcinoma, hereditary (1)
1	-	-	Astrocytoma, anaplastic;C0334586:Pleomorphic xanthoastrocytoma (1)
1	-	-	Colorectal cancer (2)
1	-	-	Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (1)
1	-	-	Li-fraumeni-like syndrome (1)
1	-	-	Ovarian neoplasm (1)
1	-	-	Squamous cell carcinoma of the head and neck (1)
1	-	-	TP53-related disorder (1)
-	-	-	Astrocytoma IDH-mutant (1)
-	-	-	Diffuse glioma, H3 G34 mutant (1)
-	-	-	Diffuse midline glioma, H3 K27M-mutant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.98
MPC		0.39
ClinPred		1.0	D
GERP RS		1.5
PromoterAI		-0.0083	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.91
gMVP		0.84
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28934574; hg19: chr17-7577094; COSMIC: COSV52662048; COSMIC: COSV52662048;