rs587782596

Variant names:

• chr17-7675071-G-A
• rs587782596
• NM_000546.6:c.541C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7675071-G-A
• chr17-7675071-G-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.541C>T​(p.Arg181Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,080 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: "SCV000186999: Yeast based functional studies have shown this alteration to have significantly reduced transactivation capacity compared to wild type, as well as dominant negative properties with several response elements (Monti P et al. Mol Cancer Res. 2011" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R181L) has been classified as Likely pathogenic. The gene TP53 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8 U:1 O:2
• Conservation: PhyloP100: 6.35
• Publications: 173 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

Specifications for TP53 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000186999: Yeast based functional studies have shown this alteration to have significantly reduced transactivation capacity compared to wild type, as well as dominant negative properties with several response elements (Monti P et al. Mol Cancer Res. 2011;9(3):271-9; IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003;8;100(14):8424-9).; SCV000911991: While some studies have shown that the mutant protein shows partial reduction of transactivation activity (IARC database and PMID: 12826609) and normal function in human cell growth suppression assays (PMID: 29979965, 30224644), other studies have shown that this variant partially or fully impairs transcriptional transactivation activity, DNA binding activity, and apoptotic activity of the TP53 protein (PMID: 10229196, 12917626, 17606709, 20128691, 20471942, 21343334).; SCV000218970: Experimental studies have shown that this missense change affects TP53 function (PMID: 11896595, 12826609, 12917626, 17606709, 20471942, 21343334).
• PM1: In a hotspot region, there are 33 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 28 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 chr17-7675070-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 39420.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 17-7675071-G-A is Pathogenic according to our data. Variant chr17-7675071-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 142624.Status of the report is reviewed_by_expert_panel, 3 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.541C>T	p.Arg181Cys	missense	Exon 5 of 11	NP_000537.3
	TP53	NM_001126112.3		c.541C>T	p.Arg181Cys	missense	Exon 5 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.541C>T	p.Arg181Cys	missense	Exon 6 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.541C>T	p.Arg181Cys	missense	Exon 5 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.541C>T	p.Arg181Cys	missense	Exon 5 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.424C>T	p.Arg142Cys	missense	Exon 4 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 33

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

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111996

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

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	Li-Fraumeni syndrome (2)
1	-	-	Adrenocortical carcinoma, hereditary (1)
1	-	-	Familial cancer of breast (1)
-	-	-	Colorectal cancer (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M
PhyloP100		6.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.015	D
Polyphen		0.77	P
Vest4		0.71
MutPred		0.93		Gain of catalytic residue at S183 (P = 0.0137)
MVP		0.98
MPC		1.3
ClinPred		0.96	D
GERP RS		5.5
PromoterAI		-0.0056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.42
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587782596; hg19: chr17-7578389; COSMIC: COSV52689134; COSMIC: COSV52689134;