GeneBe

17-7675088-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2_SupportingPS4_ModeratePS3PM1PP3PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.524G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 175 (p.Arg175His). This variant has been reported in 3 unrelated families meeting Classic and Revised Chompret criteria.Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate: 8825920, 11370630, 8164043). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in 1 family (PP1_Moderate; PMID:8825920). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID:8023157). Computational predictor scores (BayesDel = 0.54619; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has an allele frequency of 0.000005932 (7/1180032 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as [CLASSIFICATION] for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP1_Moderate, PM1, PS4_Moderate, PP3, PM2_Supporting. (Bayesian Points: 12; VCEP specifications version 2.0; 9/6/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000251/MONDO:0018875/009

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

15
2
1

Clinical Significance

Pathogenic reviewed by expert panel P:37O:8

Conservation

PhyloP100: 6.16

Publications

2762 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
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

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
TP53
NM_000546.6
MANE Select
c.524G>Ap.Arg175His
missense
Exon 5 of 11NP_000537.3
TP53
NM_001126112.3
c.524G>Ap.Arg175His
missense
Exon 5 of 11NP_001119584.1
TP53
NM_001407262.1
c.524G>Ap.Arg175His
missense
Exon 6 of 12NP_001394191.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
TP53
ENST00000269305.9
TSL:1 MANE Select
c.524G>Ap.Arg175His
missense
Exon 5 of 11ENSP00000269305.4
TP53
ENST00000445888.6
TSL:1
c.524G>Ap.Arg175His
missense
Exon 5 of 11ENSP00000391478.2
TP53
ENST00000610292.4
TSL:1
c.407G>Ap.Arg136His
missense
Exon 4 of 10ENSP00000478219.1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
33
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:
0.00
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
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251276
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461858
Hom.:
0
Cov.:
35
AF XY:
0.00000550
AC XY:
4
AN XY:
727234
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53408
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000540
AC:
6
AN:
1111992
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000735412), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.300
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74348
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41470
American (AMR)
AF:
0.00
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4838
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68040
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000153
Hom.:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

ClinVar submissions as Germline
Significance:Pathogenic
Revision:reviewed by expert panel
View on ClinVar

Computational scores

Publications

Other links and lift over

dbSNP: rs28934578; hg19: chr17-7578406; COSMIC: COSV52661038; COSMIC: COSV52661038; API