Genetic Variant TP53:p.Pro36Pro (chr17-7676261-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000546.6(TP53):c.108G>A(p.Pro36Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,614,064 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P36P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0099 ( 9 hom., cov: 31)

Exomes 𝑓: 0.013 ( 152 hom. )

Consequence

TP53
NM_000546.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:24

Conservation

PhyloP100: -1.12

Publications

58 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 17-7676261-C-T is Benign according to our data. Variant chr17-7676261-C-T is described in ClinVar as Benign. ClinVar VariationId is 132708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.12 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00988 (1503/152196) while in subpopulation NFE AF = 0.0141 (957/68024). AF 95% confidence interval is 0.0133. There are 9 homozygotes in GnomAd4. There are 676 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1503 AD gene.

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.108G>A	p.Pro36Pro	synonymous	Exon 4 of 11	NP_000537.3
TP53	NM_001126112.3		c.108G>A	p.Pro36Pro	synonymous	Exon 4 of 11	NP_001119584.1	K7PPA8
TP53	NM_001407262.1		c.108G>A	p.Pro36Pro	synonymous	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.108G>A	p.Pro36Pro	synonymous	Exon 4 of 11	ENSP00000269305.4	P04637-1
TP53	ENST00000445888.6	TSL:1	c.108G>A	p.Pro36Pro	synonymous	Exon 4 of 11	ENSP00000391478.2	P04637-1
TP53	ENST00000455263.6	TSL:1	c.108G>A	p.Pro36Pro	synonymous	Exon 4 of 12	ENSP00000398846.2	P04637-3

Frequencies

GnomAD3 genomes

AF:

0.00985

AC:

1498

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00505

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00870

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0141

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0133

AC:

3336

AN:

251286

AF XY:

0.0130

show subpopulations

Gnomad AFR exome

AF:

0.00537

Gnomad AMR exome

AF:

0.0305

Gnomad ASJ exome

AF:

0.00605

Gnomad EAS exome

AF:

0.00103

Gnomad FIN exome

AF:

0.00402

Gnomad NFE exome

AF:

0.0143

Gnomad OTH exome

AF:

0.0130

GnomAD4 exome

AF:

0.0134

AC:

19644

AN:

1461868

Hom.:

152

Cov.:

AF XY:

0.0132

AC XY:

9597

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00618

AC:

207

AN:

33480

American (AMR)

AF:

0.0275

AC:

1231

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00654

AC:

171

AN:

26136

East Asian (EAS)

AF:

0.00244

AC:

AN:

39700

South Asian (SAS)

AF:

0.0106

AC:

916

AN:

86256

European-Finnish (FIN)

AF:

0.00436

AC:

233

AN:

53412

Middle Eastern (MID)

AF:

0.0130

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0144

AC:

15995

AN:

1111998

Other (OTH)

AF:

0.0119

AC:

719

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

1208

2416

3625

4833

6041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

608

1216

1824

2432

3040

<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:

0.00988

AC:

1503

AN:

152196

Hom.:

Cov.:

AF XY:

0.00909

AC XY:

676

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00518

AC:

215

AN:

41508

American (AMR)

AF:

0.0113

AC:

173

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00836

AC:

AN:

3468

East Asian (EAS)

AF:

0.00154

AC:

AN:

5180

South Asian (SAS)

AF:

0.00871

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0141

AC:

957

AN:

68024

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

151

227

302

378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0116

Hom.:

Bravo

AF:

0.0111

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0160

EpiControl

AF:

0.0146

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Li-Fraumeni syndrome 1 (5)

Hereditary cancer-predisposing syndrome (4)

not provided (4)

Hereditary breast ovarian cancer syndrome (2)

Li-Fraumeni syndrome (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

9.8

(source)

DANN

Benign

0.36

PhyloP100

-1.1

PromoterAI

-0.0033

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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