17-7675130-G-T

Position:

chr17-7675130-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000546.6(TP53):c.482C>A(p.Ala161Asp) variant causes a missense change involving the alteration of a 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

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: 10.0

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 9 ACMG points.

PM1

In a strand (size 9) in uniprot entity P53_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000546.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

PP5

Variant 17-7675130-G-T is Pathogenic according to our data. Variant chr17-7675130-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422295.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.482C>A	p.Ala161Asp	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.482C>A	p.Ala161Asp	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:

1461886

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Mar 12, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16541312, 26895810, 11715068, 29979965, 10519380, 11590071, 16322298, 14559903, 26271412, 21071467, 12826609, 24836762, 26514544, 17121883, 30224644, 22768918, 15510160, 23117049) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2024

The p.A161D variant (also known as c.482C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 482. The alanine at codon 161 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been reported in blood specimens from breast and ovarian cancer patients (Dorling et al. N Engl J Med. 2021 02;384:428-439; Weber-Lassalle K et al. Hum Mutat, 2018 12;39:2040-2046), as well as breast and ovarian tumors (Hagio K et al. Sci Rep, 2021 04;11:8109; Sanders BE et al. Technol Cancer Res Treat;20:15330338211027917). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). 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 variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). Another alteration at the same codon, p.A161T (c.481G>A), has been observed in multiple families with clinical histories consistent with a diagnosis of Li-Fraumeni syndrome (LFS) (Freitas AC et al. Ecancermedicalscience. 2018 Jan;12:804; Ambry internal data). In addition, the p.A161D alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Li-Fraumeni syndrome

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 22, 2017

In summary, this variant is a rare missense change with that disrupts protein function in yeast and is absent from the population, but has also not been reported in the germline of any affected individual. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An experimental study has shown that this missense change disrupts TP53 transactivational activity in yeast (PMID: 12826609). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature as a germline variant in individuals with a TP53-related disease. This sequence change replaces alanine with aspartic acid at codon 161 of the TP53 protein (p.Ala161Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

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

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.85

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

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.95

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

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.0

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

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.9

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

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.0060

D;D;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

0.83

MutPred

0.77

Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);.;.;.;.;.;.;.;Loss of sheet (P = 0.0357);.;Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);.;.;Loss of sheet (P = 0.0357);.;.;.;.;Loss of sheet (P = 0.0357);

MVP

0.99

MPC

2.0

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.84

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