NM_000546.6:c.100C>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBP6

The NM_000546.6(TP53):c.100C>A(p.Pro34Thr) 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 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P34S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: -2.06

Publications

7 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: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 24 uncertain in NM_000546.6

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08877042).

BP6

Variant 17-7676269-G-T is Benign according to our data. Variant chr17-7676269-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 185157.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.100C>A	p.Pro34Thr	missense_variant	Exon 4 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.100C>A	p.Pro34Thr	missense_variant	Exon 4 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

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:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:2Benign:1

Apr 30, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 34 of the TP53 protein (p.Pro34Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 185157). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Apr 27, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces proline with threonine at codon 34 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant does not impact function in yeast transactivation assays and human cell growth suppression assays (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Feb 02, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Mar 04, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Li-Fraumeni syndrome 1

Uncertain:1

Aug 16, 2021

MGZ Medical Genetics Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Apr 11, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: transactivation and growth suppression activity comparable to wild type (Kato 2003, Giacomelli 2018); This variant is associated with the following publications: (PMID: 12826609, 30224644, 30886117, 15510160, Pessoa2014[Chapter])

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Benign

-0.10

CADD

Benign

0.0070

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.0057

T;T;T;.;.;.;T;.;T;T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.68

T;T;.;T;T;.;T;T;T;T;T

M_CAP

Benign

0.075

MetaRNN

Benign

0.089

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

0.0

.;.;N;N;N;N;N;.;.;.;.

PhyloP100

-2.1

PROVEAN

Benign

0.22

N;N;N;.;N;N;N;.;N;.;N

REVEL

Uncertain

0.43

Sift

Benign

0.18

T;T;T;.;T;T;T;.;T;.;T

Sift4G

Benign

0.38

T;T;T;T;T;T;T;T;.;T;.

Vest4

0.049

ClinPred

0.094

GERP RS

-5.3

PromoterAI

-0.0042

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.24

gMVP

0.23

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over