dbSNP rs1800371: TP53:p.Pro47Ser (chr17-7676230-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BA1BP4BS3BS2

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.139C>T variant in TP53 is a missense variant predicted to cause substitution of Proline by Serine at amino acid 47 (p.Pro47Ser). The filtering allele frequency of the c.139C>T variant in the TP53 gene is 0.01560 for African/African American population by gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.001) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BA1 (Bayesian Points: N/A; VCEP specifications version 2.0; 7/24/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000053/MONDO:0018875/009

Frequency

Genomes: 𝑓 0.0046 ( 8 hom., cov: 31)

Exomes 𝑓: 0.00048 ( 6 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:22O:2

Conservation

PhyloP100: -3.33

Publications

171 publications found

Variant links:

COSMIC-nc: COSV53150763

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 -17 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

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.139C>T	p.Pro47Ser	missense	Exon 4 of 11	NP_000537.3
TP53	NM_001126112.3		c.139C>T	p.Pro47Ser	missense	Exon 4 of 11	NP_001119584.1	K7PPA8
TP53	NM_001407262.1		c.139C>T	p.Pro47Ser	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.139C>T	p.Pro47Ser	missense	Exon 4 of 11	ENSP00000269305.4	P04637-1
TP53	ENST00000445888.6	TSL:1	c.139C>T	p.Pro47Ser	missense	Exon 4 of 11	ENSP00000391478.2	P04637-1
TP53	ENST00000610292.4	TSL:1	c.22C>T	p.Pro8Ser	missense	Exon 3 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes

AF:

0.00460

AC:

699

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00125

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:

0.0000294

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00123

AC:

310

AN:

251372

AF XY:

0.000971

show subpopulations

Gnomad AFR exome

AF:

0.0167

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000483

AC:

706

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000441

AC XY:

321

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0167

AC:

558

AN:

33480

American (AMR)

AF:

0.00123

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1112010

Other (OTH)

AF:

0.00119

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

100

151

201

251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00459

AC:

698

AN:

152198

Hom.:

Cov.:

AF XY:

0.00441

AC XY:

328

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0161

AC:

669

AN:

41510

American (AMR)

AF:

0.00124

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68004

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

129

161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00368

Hom.:

Bravo

AF:

0.00556

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0152

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00171

AC:

208

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (4)

Hereditary cancer-predisposing syndrome (3)

Li-Fraumeni syndrome (3)

Li-Fraumeni syndrome 1 (3)

Hereditary breast ovarian cancer syndrome (2)

Breast and/or ovarian cancer (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)

Malignant tumor of breast (1)

Cervical cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.21

CADD

Benign

0.021

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.0044

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0042

MetaSVM

Pathogenic

0.79

MutationAssessor

Benign

0.97

PhyloP100

-3.3

PrimateAI

Benign

0.27

PROVEAN

Benign

0.26

REVEL

Uncertain

0.32

Sift

Benign

0.18

Sift4G

Benign

0.24

Polyphen

0.0050

Vest4

0.11

MVP

0.81

MPC

0.65

ClinPred

0.0047

GERP RS

-7.9

PromoterAI

-0.0071

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.33

gMVP

0.35

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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