rs786201659

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. BS3BS2_SupportingPP3

This summary comes from the ClinGen Evidence Repository: This variant has a BayesDel score >0.16 and Align GVGD (Zebrafish) is Class 25 or higher (PP3). This variant has been observed in 3 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). Transactivation assays show [retained/supertransactivation] function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID:12826609, 30224644). In this case, a single supporting evidence code (PP3) should not be considered conflicting evidence as variant otherwise meets criteria for Likely Benign classification. In summary, TP53 c.997C>T (p.Arg333Cys) 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: PP3, BS2_Supporting, BS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000530/MONDO:0007903/009

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:8B:3

Conservation

PhyloP100: 2.57

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 -4 ACMG points.

PP3

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.997C>T	p.Arg333Cys	missense_variant	10/11	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.997C>T	p.Arg333Cys	missense_variant	10/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

250508

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135458

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461360

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726968

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000243

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000896

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:8Benign:3

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	Nov 30, 2023	This missense variant replaces arginine with cysteine at codon 333 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). Experimental studies have reported for this variant behaves as wildtype in a yeast-based transcriptional transactivation assay and a human cell growth suppression assay (PMID: 12826609, 30224644), but demonstrated intermediate level activity in a colony suppression assay (PMID: 30840781). This variant has been reported in an individual affected with early-onset breast cancer (PMID: 33128190) and an individual affected with Ewing sarcoma and leukemia (IARC database, PMID: 27328919). This variant has been identified in 6/250508 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	Dec 28, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 333 of the TP53 protein (p.Arg333Cys). This variant is present in population databases (rs769934890, gnomAD 0.004%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia, breast cancer, Ewing sarcoma, pancreatic cancer, and/or rectal cancer (PMID: 23894400, 31321604, 33128190). ClinVar contains an entry for this variant (Variation ID: 184745). 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, 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	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 05, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2019	Not observed at a significant frequency 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: 22187033, 24030381, 30352134, 28861920, 16007150, 26572807, 23894400, 27834926, 27347428, 28993836, 28098136, 14559903, 12826609, 29955864, 30840781, 31016814, 31321604) -

Li-Fraumeni syndrome 1

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Apr 19, 2021	This variant has a BayesDel score >0.16 and Align GVGD (Zebrafish) is Class 25 or higher (PP3). This variant has been observed in 3 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). Transactivation assays show [retained/supertransactivation] function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In this case, a single supporting evidence code (PP3) should not be considered conflicting evidence as variant otherwise meets criteria for Likely Benign classification. In summary, TP53 c.997C>T (p.Arg333Cys) 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: PP3, BS2_Supporting, BS3. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 01, 2023	This missense variant replaces arginine with cysteine at codon 333 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). Experimental studies have reported for this variant behaves as wildtype in a yeast-based transcriptional transactivation assay and a human cell growth suppression assay (PMID: 12826609, 30224644), but demonstrated intermediate level activity in a colony suppression assay (PMID: 30840781). This variant has been reported in an individual affected with early-onset breast cancer (PMID: 33128190) and an individual affected with Ewing sarcoma and leukemia (IARC database, PMID: 27328919). This variant has been identified in 6/250508 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2021	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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 13, 2018

Variant summary: TP53 c.997C>T (p.Arg333Cys) results in a non-conservative amino acid change located in the p53, tetramerisation domain (IPR010991) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 245334 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.997C>T, has been reported in the literature in an individual affected with acute lymphoblastic leukemia (ALL) and Ewing sarcoma, who met the Chompret criteria for Li-Fraumeni Syndrome (Mitchell 2013). This report however does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome (LFS). In a study evaluating an impact on protein function, the variant protein was found to be able to form tetramers and had a partial transcriptional activity (Kawaguchi 2005), however these data do not allow convincing conclusions about the variant effect. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

TP53-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2023

The TP53 c.997C>T variant is predicted to result in the amino acid substitution p.Arg333Cys. This variant has been reported in patients with adult onset sarcoma, rectal and pancreatic cancer, and breast and/or ovarian cancer, although pathogenicity was not established in these cases (Mitchell et al. 2013. PubMed ID: 23894400; Bittar et al. 2019. PubMed ID: 31321604; Gomes et al. 2020. PubMed ID: 33128190). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7574030-G-A). This variant is interpreted as likely benign by the ClinGen TP53 Variant Curation Expert Panel, in part based on detection of this variant in 3 individuals over the age of 60 without cancer and functional studies not supporting a deleterious effect (https://www.ncbi.nlm.nih.gov/clinvar/variation/184745/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Squamous cell carcinoma of the head and neck

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

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

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.97

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

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.97

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

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

MutationTaster

Benign

0.99

D;D;D;D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.6

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

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.86

MutPred

0.85

.;.;.;Loss of MoRF binding (P = 0.0174);.;Loss of MoRF binding (P = 0.0174);.;.;

MVP

0.96

MPC

0.43

ClinPred

0.89

GERP RS

4.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.88

gMVP

0.66

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