17-7675181-T-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000546.6(TP53):c.431A>C(p.Gln144Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 4.04

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.431A>C	p.Gln144Pro	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.431A>C	p.Gln144Pro	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Jan 12, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q144P pathogenic mutation (also known as c.431A>C), located in coding exon 4 of theTP53 gene, results from an A to C substitution at nucleotide position 431. The glutamine at codon 144 is replaced by proline, an amino acid with similar properties. This variant is located in the DNA binding domain of the TP53 protein, 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). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ovarian neoplasm

Pathogenic:1

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Li-Fraumeni syndrome 1

Uncertain:1

Jun 18, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome

Uncertain:1

Nov 25, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine with proline at codon 144 of the TP53 protein (p.Gln144Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 186594). Experimental studies have shown that this variant affects TP53 protein function (PMID: 12826609, 30224644, 29979965). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

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

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.93

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;.;.;.;.;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.5

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

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0070

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

Polyphen

1.0

D;.;.;.;.;.;D;.;D;B;D;.;.;D;.;.;.;D;.;.

Vest4

0.83

MutPred

0.79

Loss of catalytic residue at Q144 (P = 0.0123);Loss of catalytic residue at Q144 (P = 0.0123);.;.;.;.;Loss of catalytic residue at Q144 (P = 0.0123);.;Loss of catalytic residue at Q144 (P = 0.0123);Loss of catalytic residue at Q144 (P = 0.0123);Loss of catalytic residue at Q144 (P = 0.0123);.;.;Loss of catalytic residue at Q144 (P = 0.0123);.;.;.;.;Loss of catalytic residue at Q144 (P = 0.0123);.;

MVP

0.98

MPC

1.8

ClinPred

1.0

GERP RS

5.5

Varity_R

0.98

gMVP

0.87

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over