rs770374782

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS2_SupportingBS3

This summary comes from the ClinGen Evidence Repository: Transactivation assays show retained function according to Kato, et al (PMID:12826609) and there is no evidence of a dominant negative effect or loss of function according to Giacomelli et al. (PMID:30224644) and Kotler et al. (PMID:29979965) (BS3). Additionally, this variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C15 (BP4). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). In summary, TP53 c.868C>T; p.Arg290Cys meets criteria to be classified as Likely Benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3; BP4; BS2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA001448/MONDO:0007903/009

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:5B:2

Conservation

PhyloP100: 3.72

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 Likely_benign. Variant got -6 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.868C>T	p.Arg290Cys	missense_variant	8/11	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.868C>T	p.Arg290Cys	missense_variant	8/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251486

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:5Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	This missense variant replaces arginine with cysteine at codon 290 of the TP53 protein. Computational prediction suggests that this variant may impact protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to function normally in yeast transactivation assays (PMID: 12826609) and human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with early-onset breast cancer (PMID: 25503501) and osteosarcoma (PMID: 25512523). This variant has been identified in 4/282870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 290 of the TP53 protein (p.Arg290Cys). This variant is present in population databases (rs770374782, gnomAD 0.005%). This missense change has been observed in individual(s) with breast cancer and/or osteosarcoma (PMID: 25503501, 25512523). ClinVar contains an entry for this variant (Variation ID: 216472). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 17311302, 29979965, 30224644). 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. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2019	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12909720, 25589618, 8338955, 24729566, 23718828, 24113472, 21159888, 22205265, 22568511, 18843282, 17311302, 23200980, 19533719, 21643842, 25256751, 21118481, 22678923, 27101868, 28502725, 28861920, 30483911, 25503501, 25512523, 29625052, 29979965, 30720243, 30840781) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 16, 2023	In the published literature, it has been reported individuals with early-onset breast cancer patient (PMID: 25503501 (2015)), lung cancer (PMID: 29625052 (2018)), and pancreatic cancer (PMID: 23200980 (2013)). Functional studies have shown the variant to retain transactivation activity and retaining anti-proliferative activity (IARC TP53 (https://p53.iarc.fr/), PMID: 12826609 (2003), 17311302 (2007), 29979965 (2018)). The frequency of this variant in the general population, 0.000014 (4/282870 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 04, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 12, 2023	This missense variant replaces arginine with cysteine at codon 290 of the TP53 protein. Computational prediction suggests that this variant may impact protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to function normally in yeast transactivation assays (PMID: 12826609) and human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with early-onset breast cancer (PMID: 25503501) and osteosarcoma (PMID: 25512523). This variant has been identified in 4/282870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Li-Fraumeni syndrome 1

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen TP53 Variant Curation Expert Panel, ClinGen

May 13, 2021

Transactivation assays show retained function according to Kato, et al (PMID: 12826609) and there is no evidence of a dominant negative effect or loss of function according to Giacomelli et al. (PMID: 30224644) and Kotler et al. (PMID: 29979965) (BS3). Additionally, this variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C15 (BP4). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). In summary, TP53 c.868C>T; p.Arg290Cys meets criteria to be classified as Likely Benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3; BP4; BS2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

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

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

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

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.87

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;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.22

PROVEAN

Pathogenic

-4.7

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

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0050

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

Polyphen

0.99, 0.99, 0.93

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

Vest4

0.51

MVP

0.95

MPC

0.38

ClinPred

0.89

GERP RS

4.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.50

gMVP

0.37

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