17-7676154-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000546.6(TP53):c.215C>G(p.Pro72Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,613,582 control chromosomes in the GnomAD database, including 411,964 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P72L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.63 ( 31776 hom., cov: 31)

Exomes 𝑓: 0.72 ( 380188 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:1B:30O:3

Conservation

PhyloP100: 1.44

Publications

2091 publications found

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 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

TP53 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.0827485E-6).

BP6

Variant 17-7676154-G-C is Benign according to our data. Variant chr17-7676154-G-C is described in ClinVar as Benign. ClinVar VariationId is 12351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TP53	NM_000546.6	MANE Select	c.215C>G	p.Pro72Arg	missense	Exon 4 of 11	NP_000537.3
TP53	NM_001126112.3		c.215C>G	p.Pro72Arg	missense	Exon 4 of 11	NP_001119584.1	K7PPA8
TP53	NM_001407262.1		c.215C>G	p.Pro72Arg	missense	Exon 5 of 12	NP_001394191.1	K7PPA8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TP53	ENST00000269305.9	TSL:1 MANE Select	c.215C>G	p.Pro72Arg	missense	Exon 4 of 11	ENSP00000269305.4	P04637-1
TP53	ENST00000445888.6	TSL:1	c.215C>G	p.Pro72Arg	missense	Exon 4 of 11	ENSP00000391478.2	P04637-1
TP53	ENST00000610292.4	TSL:1	c.98C>G	p.Pro33Arg	missense	Exon 3 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes

AF:

0.627

AC:

95293

AN:

151904

Hom.:

31786

Cov.:

show subpopulations

Gnomad AFR

AF:

0.388

Gnomad AMI

AF:

0.670

Gnomad AMR

AF:

0.699

Gnomad ASJ

AF:

0.721

Gnomad EAS

AF:

0.577

Gnomad SAS

AF:

0.521

Gnomad FIN

AF:

0.736

Gnomad MID

AF:

0.662

Gnomad NFE

AF:

0.745

Gnomad OTH

AF:

0.660

GnomAD2 exomes

AF:

0.668

AC:

167398

AN:

250534

AF XY:

0.664

show subpopulations

Gnomad AFR exome

AF:

0.380

Gnomad AMR exome

AF:

0.715

Gnomad ASJ exome

AF:

0.715

Gnomad EAS exome

AF:

0.570

Gnomad FIN exome

AF:

0.730

Gnomad NFE exome

AF:

0.738

Gnomad OTH exome

AF:

0.698

GnomAD4 exome

AF:

0.716

AC:

1046941

AN:

1461558

Hom.:

380188

Cov.:

AF XY:

0.710

AC XY:

516401

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.376

AC:

12577

AN:

33470

American (AMR)

AF:

0.714

AC:

31948

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.719

AC:

18801

AN:

26136

East Asian (EAS)

AF:

0.605

AC:

24013

AN:

39700

South Asian (SAS)

AF:

0.507

AC:

43687

AN:

86236

European-Finnish (FIN)

AF:

0.733

AC:

39131

AN:

53416

Middle Eastern (MID)

AF:

0.604

AC:

3329

AN:

5516

European-Non Finnish (NFE)

AF:

0.748

AC:

831482

AN:

1111994

Other (OTH)

AF:

0.695

AC:

41973

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

19271

38542

57813

77084

96355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20114

40228

60342

80456

100570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.627

AC:

95285

AN:

152024

Hom.:

31776

Cov.:

AF XY:

0.625

AC XY:

46413

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.387

AC:

16028

AN:

41460

American (AMR)

AF:

0.700

AC:

10669

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.721

AC:

2499

AN:

3468

East Asian (EAS)

AF:

0.576

AC:

2971

AN:

5162

South Asian (SAS)

AF:

0.523

AC:

2518

AN:

4814

European-Finnish (FIN)

AF:

0.736

AC:

7782

AN:

10578

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.745

AC:

50641

AN:

67974

Other (OTH)

AF:

0.652

AC:

1376

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1665

3331

4996

6662

8327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

764

1528

2292

3056

3820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.714

Hom.:

27610

Bravo

AF:

0.617

TwinsUK

AF:

0.755

AC:

2801

ALSPAC

AF:

0.750

AC:

2889

ESP6500AA

AF:

0.405

AC:

1784

ESP6500EA

AF:

0.745

AC:

6409

ExAC

AF:

0.659

AC:

79937

Asia WGS

AF:

0.514

AC:

1788

AN:

3476

EpiCase

AF:

0.750

EpiControl

AF:

0.745

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Li-Fraumeni syndrome 1 (7)

not specified (8)

Hereditary cancer-predisposing syndrome (5)

not provided (4)

Li-Fraumeni syndrome (3)

Hereditary breast ovarian cancer syndrome (2)

Acute myeloid leukemia (1)

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 (1)

Lip and oral cavity carcinoma (1)

TP53 POLYMORPHISM (1)

Cervical cancer (1)

Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.013

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0000081

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

PhyloP100

1.4

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.29

REVEL

Uncertain

0.37

Sift

Benign

0.26

Sift4G

Benign

0.57

Polyphen

0.74

Vest4

0.16

MPC

0.81

ClinPred

0.0069

GERP RS

1.9

PromoterAI

-0.079

Neutral

(source)

Varity_R

0.086

gMVP

0.21

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over