17-7675148-G-T

Position:

chr17-7675148-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000546.6(TP53):c.464C>A(p.Thr155Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 1.20

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:

TP53 (HGNC:):

TP53 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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, 0.932

PP5

Variant 17-7675148-G-T is Pathogenic according to our data. Variant chr17-7675148-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 406564.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.464C>A	p.Thr155Asn	missense_variant	5/11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.464C>A	p.Thr155Asn	missense_variant	5/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 02, 2022	Variant summary: TP53 c.464C>A (p.Thr155Asn) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251290 control chromosomes. In addition to being widely reported in a variety of somatic cancers, c.464C>A has been reported in the literature as a reportedly germline variant in settings of glioma and breast cancer and (example, Kyritsis_1994, Nandikolla_2017). At least one publication reports experimental evidence evaluating an impact on protein function (example, Kato_2003). The most pronounced variant effect results in non-functional outcome based on overall transcription activity (TA) on eight different promoters as measured in yeast assays. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 20, 2022	Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 406564). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 8308926; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 155 of the TP53 protein (p.Thr155Asn). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Li-Fraumeni syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 14, 2024

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 25, 2022

Published functional studies demonstrate a damaging effect: non-functional transactivation and dominant negative effect (Monti 2011, Giacomelli 2018, Kotler 2018); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with TP53-related cancers (Kyritsis 1994, Nandikolla 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29979965, 15510160, 26718964, 25149524, 15781632, 32850382, 30840781, 17606709, 21343334, 30224644, 28356770, 24113472, 8308926, 32321992, 30720243) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2022

The p.T155N pathogenic mutation (also known as c.464C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 464. The threonine at codon 155 is replaced by asparagine, an amino acid with similar properties. This alteration has been detected in several individuals meeting the revised Chompret criteria (Kyritsis A et al. J. Natl. Cancer Inst. 1994 Mar; 86(5):344-9; Nandikolla A et al. Breast Cancer (Dove Med Press) 2017; 9 207-215; Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have a loss of transactivation in yeast-based assays (Monti P et al. Mol. Cancer Res. 2011 Mar; 9(3):271-9; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Smardova J et al. Oncol. Rep. 2016 Mar;35:1859-67). Studies conducted in human cell lines indicate this alteration has dominant-negative activity and is deficient at growth suppression (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). The threonine at codon 155 is a target of phosphorylation, which may be an important regulatory step for maintaining appropriate levels of p53 protein in the cell (Bech-Otschir D et al. EMBO J. 2001 Apr; 20(7):1630-9). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jan 19, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Uncertain

0.67

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

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.93

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

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

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.2

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

REVEL

Uncertain

0.55

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.0090

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

Polyphen

0.95

P;.;.;.;.;.;B;.;P;B;P;.;.;B;.;.;.;P;.

Vest4

0.71

MutPred

0.89

Loss of phosphorylation at T155 (P = 0.0156);Loss of phosphorylation at T155 (P = 0.0156);.;.;.;.;Loss of phosphorylation at T155 (P = 0.0156);.;Loss of phosphorylation at T155 (P = 0.0156);Loss of phosphorylation at T155 (P = 0.0156);Loss of phosphorylation at T155 (P = 0.0156);.;.;Loss of phosphorylation at T155 (P = 0.0156);.;.;.;.;Loss of phosphorylation at T155 (P = 0.0156);

MVP

0.87

MPC

1.5

ClinPred

0.64

GERP RS

-0.47

Varity_R

0.79

gMVP

0.45

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