rs886039483

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The ENST00000269305.9(TP53):c.376T>G(p.Tyr126Asp) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. Y126C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

TP53
ENST00000269305.9 missense, splice_region

Scores

Splicing: ADA: 0.8129

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 9.28

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in ENST00000269305.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7675235-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458541.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=4}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

PP5

Variant 17-7675236-A-C is Pathogenic according to our data. Variant chr17-7675236-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265333.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.376T>G	p.Tyr126Asp	missense_variant, splice_region_variant	5/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.376T>G	p.Tyr126Asp	missense_variant, splice_region_variant	5/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 13, 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]. -

Li-Fraumeni syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 31, 2023

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. Experimental studies have shown that this missense change affects TP53 function (PMID: 11229518, 11429705, 12826609, 29979965, 30224644). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 265333). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 126 of the TP53 protein (p.Tyr126Asp). -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 03, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29979965, 11896595, 20668451, 21343334, 22006311, 28234344, 27189670, 14559903, 12826609, 11429705, 11229518, 21796119, 23525077, 23297126, 23103869) -

Ovarian neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2017

The p.Y126D variant (also known as c.376T>G) is located in coding exon 4 of the TP53 gene. The tyrosine at codon 126 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This change occurs in the first base pair of coding exon 4. This alteration has been reported in an individual with a personal history of both breast and peritoneal cancer and a family history of breast or ovarian cancer (Walsh T et al. Proc. Natl. Acad. Sci. U.S.A., 2011 Nov;108:18032-7). This variant is located in the DNA binding domain of the TP53 protein and is reported to exhibit loss of transactivation capacity in yeast-based functional studies. (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Campomenosi P et al. Oncogene, 2001 Jun;20:3573-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

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

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.97

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

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.3

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-8.5

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

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.94

MutPred

0.84

Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;Loss of sheet (P = 0.0457);.;Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;.;Loss of sheet (P = 0.0457);.;.;.;Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);

MVP

1.0

MPC

2.2

ClinPred

1.0

GERP RS

5.5

Varity_R

0.99

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.81

dbscSNV1_RF

Benign

0.69

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