17-7676155-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.214C>G variant in TP53 is a missense variant predicted to cause substitution of proline by alanine at amino acid 72 (p.Pro72Ala).This is a polymorphic residue (alternate nomenclature: p.Arg72). This variant received a total of 0.5 points in one individual. (PS4 not met; Internal lab contributors). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor). In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = -0.215412; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BP4_Moderate. (Bayesian Points: -4; VCEP specifications version 2.2; 2/6/2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000070/MONDO:0018875/009

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:11B:1

Conservation

PhyloP100: -0.364

Publications

78 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: Likely_benign. The variant received -5 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.

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.214C>G	p.Pro72Ala	missense	Exon 4 of 11	NP_000537.3
TP53	NM_001126112.3		c.214C>G	p.Pro72Ala	missense	Exon 4 of 11	NP_001119584.1	K7PPA8
TP53	NM_001407262.1		c.214C>G	p.Pro72Ala	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.214C>G	p.Pro72Ala	missense	Exon 4 of 11	ENSP00000269305.4	P04637-1
TP53	ENST00000445888.6	TSL:1	c.214C>G	p.Pro72Ala	missense	Exon 4 of 11	ENSP00000391478.2	P04637-1
TP53	ENST00000610292.4	TSL:1	c.97C>G	p.Pro33Ala	missense	Exon 3 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250672

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461550

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5538

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111948

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41412

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000385

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Li-Fraumeni syndrome (3)

Hereditary cancer-predisposing syndrome (2)

Li-Fraumeni syndrome 1 (2)

not provided (2)

Choroid plexus papilloma;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;C2931038:Familial pancreatic carcinoma;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5 (1)

Familial pancreatic carcinoma (1)

TP53-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.22

CADD

Benign

0.33

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.0068

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.56

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.067

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

0.46

PhyloP100

-0.36

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.13

REVEL

Uncertain

0.32

Sift

Benign

0.48

Sift4G

Benign

0.93

Polyphen

0.0030

Vest4

0.16

MutPred

0.17

Loss of catalytic residue at P71 (P = 0.0255)

MVP

0.72

MPC

0.62

ClinPred

0.0066

GERP RS

0.24

PromoterAI

-0.031

Neutral

(source)

Varity_R

0.072

gMVP

0.16

Mutation Taster

=94/6

polymorphism

(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

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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