chr17-7675211-A-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000546.6(TP53):c.401T>G(p.Phe134Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F134V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.14

Publications

61 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

TP53 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 41 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 38 uncertain in NM_000546.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7675212-A-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 988615.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 17-7675211-A-C is Pathogenic according to our data. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675211-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 230477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.401T>G	p.Phe134Cys	missense_variant	Exon 5 of 11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.401T>G	p.Phe134Cys	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250942

AF XY:

0.00

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727200

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:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111964

Other (OTH)

AF:

0.00

AC:

AN:

60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Pathogenic:1

Jan 31, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Apr 09, 2013

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Feb 10, 2015

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.F134C variant (also known as c.401T>G), located in coding exon 4 of the TP53 gene, results from a T to G substitution at nucleotide position 401. The phenylalanine at codon 134 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Structural analysis indicates F134 is a core residue that supports residues responsible for binding DNA. Mutation at this position results in large instability within this region (Bullock AN, Nat. Rev. Cancer 2001 Oct; 1(1):68-76). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0003% (greater than 250000 alleles tested) in our clinical cohort. This amino acid position is well conserved through mammals. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D;T

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.0

.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.;.

PhyloP100

3.1

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.9

D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.;D

Polyphen

1.0

D;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D;.;.

Vest4

0.70

MutPred

0.88

Loss of catalytic residue at F134 (P = 0.0639);Loss of catalytic residue at F134 (P = 0.0639);.;.;.;.;Loss of catalytic residue at F134 (P = 0.0639);.;Loss of catalytic residue at F134 (P = 0.0639);Loss of catalytic residue at F134 (P = 0.0639);Loss of catalytic residue at F134 (P = 0.0639);.;.;Loss of catalytic residue at F134 (P = 0.0639);.;.;.;.;Loss of catalytic residue at F134 (P = 0.0639);.;

MVP

0.99

MPC

2.0

ClinPred

0.99

GERP RS

4.4

PromoterAI

-0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.83

Mutation Taster

=0/100

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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