rs1057519986

Positions:

Variant summary

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

The NM_000546.6(TP53):c.809T>G(p.Phe270Cys) 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: 31)

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.29

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a strand (size 10) in uniprot entity P53_HUMAN there are 6 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, 0.952

PP5

Variant 17-7673811-A-C is Pathogenic according to our data. Variant chr17-7673811-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376597.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=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.809T>G	p.Phe270Cys	missense_variant	8/11	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.809T>G	p.Phe270Cys	missense_variant	8/11	1	NM_000546.6	ENSP00000269305.4		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 20, 2024

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7651740, 10713666, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Adrenocortical carcinoma, hereditary

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 22, 2023

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 28, 2022

Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression ability, and dominant negative effect (Kato et al., 2003; Dearth et al., 2007; Giacomelli et al., 2018; Kotler et al., 2018); 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; Reported in the literature in families with Li-Fraumeni syndrome (Gao et al., 2020); This variant is associated with the following publications: (PMID: 15510160, 26619011, 32817165, 32358561, 29979965, 28160562, 30808373, 27662657, 16861262, 15308588, 30224644, 12826609) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 21, 2023

This missense variant replaces phenylalanine with cysteine at codon 270 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant is defective in transcriptional transactivation of TP53 target genes, displays loss of function and dominant negative activity in human cell growth suppression assays, and is non-functional in human cell proliferation assays (PMID: 12826609, 29979965, 30224644). This variant has been observed germline in two individuals suspected of having Li-Fraumeni syndrome (PMID: 32817165). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Li-Fraumeni syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 26, 2022

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 270 of the TP53 protein (p.Phe270Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 32817165). ClinVar contains an entry for this variant (Variation ID: 376597). 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. 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

0.96

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

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

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.95

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

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.5

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

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-7.1

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

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

D;T;T;T;T;T;T;D;D;D;D;D;D;D;D;D;D;D;T

Polyphen

1.0, 0.71

.;.;.;.;.;.;.;.;D;.;D;P;D;.;.;D;.;.;.

Vest4

0.63

MutPred

0.79

Loss of catalytic residue at F270 (P = 0.0121);.;.;.;.;.;.;.;Loss of catalytic residue at F270 (P = 0.0121);.;Loss of catalytic residue at F270 (P = 0.0121);Loss of catalytic residue at F270 (P = 0.0121);Loss of catalytic residue at F270 (P = 0.0121);.;.;Loss of catalytic residue at F270 (P = 0.0121);.;.;.;

MVP

1.0

MPC

0.45

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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