17-7670711-C-T

Position:

chr17-7670711-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BS2_SupportingBS3BP4

This summary comes from the ClinGen Evidence Repository: This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Transactivation assays show functional transactivation according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. and normal tetramer formation according to Kawaguchi, et al. (BS3; PMID:12826609, 30224644,16007150). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Invitae). In summary, TP53 c.998G>A (p.Arg333His) 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/CA000533/MONDO:0007903/009

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:8B:4

Conservation

PhyloP100: 1.65

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

BS2

BS3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.998G>A	p.Arg333His	missense_variant	10/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.998G>A	p.Arg333His	missense_variant	10/11	1	NM_000546.6	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000439

AC:

AN:

250566

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135482

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000656

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461464

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:8Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Feb 13, 2019	Data included in classification: Kato et al 2003: functional on yeast based assay (PMID: 12826609). Giacomelli et al, 2018 IARC No DNE and no LOF (PMID: 30224644). (BS3_strong). Data not included in classification: UK family 1: 40yo female with brain tumour at 32 & breast cancer (ER+, HER2-) at 39, variant found in unaffected mother (aged 62) mat grandmother breast cancer at 55 (deceased). The variant was observed in 6/64,339 GNOMAD NFE controls and 6/76,647 individuals in the remainder of the GNOMAD population. 5 recent classifications of variant as VUS on ClinVar. R333C recorded in an adult onset sarcoma - Mitchell (2013) PloS One 8:e69026. Mutations in tetramerisation domain cause defects in tetramer formation leading to loss of function. Fortuno et al, 2018 Bayesdel -0.092, suggested prediction: benign (PMID: 29775997). In silico tools conflicting. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This missense variant replaces arginine with histidine at codon 333 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that the mutant protein is functional in a transactivation assay (PMID 12826609) and in a cell growth suppression assay (PMID: 30224644). This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 12/281972 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

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 11, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 07, 2017	- -
Likely benign, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	May 06, 2021	This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Transactivation assays show functional transactivation according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. and normal tetramer formation according to Kawaguchi, et al. (BS3; PMID: 12826609, 30224644,16007150). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Invitae). In summary, TP53 c.998G>A (p.Arg333His) 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. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 13, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 09, 2023	This missense variant replaces arginine with histidine at codon 333 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that the mutant protein is functional in a transactivation assay (PMID 12826609) and in a cell growth suppression assay (PMID: 30224644). This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 12/281972 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	Jun 14, 2022	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 provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2021

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: functional transactivation, no dominant negative effect, intact growth suppression, and retained ability to form tetramers (Kato 2003, Kawaguchi 2005, Giacomelli 2018); Observed in an individual with multiple primary melanomas (Li 2020); This variant is associated with the following publications: (PMID: 26681312, 16007150, 23894400, 24665023, 27844328, 25148578, 9380731, 28446506, 28028119, 30224644, 28861920, 31567591, 32170000, 32980694, 15510160) -

TP53-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 13, 2023

The TP53 c.998G>A variant is predicted to result in the amino acid substitution p.Arg333His. This variant was reported in two individuals from a Li Fraumeni cohort; however, pathogenicity was not established (de Andrade KC et al 2017. PubMed ID: 28861920). This variant was also reported as a variant of uncertain significance in a patient with melanoma (Li et al 2020. PubMed ID: 31567591) and also in a thymic carcinoma tumor at 51% read fraction (Enkner F et al 2016. PubMed ID: 27844328). Functional studies indicate this variant may not impact protein function (Kato S et al 2003. PubMed ID: 12826609; Kawaguchi T et al 2005. PubMed ID: 16007150). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7574029-C-T). This variant is also reported in ClinVar as uncertain and and ClinGen expert panel interpreted this variant as likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/142273/). Although we suspect this variant could be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Feb 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.95

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

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.85

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

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.48

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.3

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

MutationTaster

Benign

0.99

D;D;D;D;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.8

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

REVEL

Uncertain

0.55

Sift

Benign

0.043

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

Sift4G

Uncertain

0.051

T;T;T;T;T;T;T;T

Polyphen

0.062

.;.;.;B;.;B;.;.

Vest4

0.36

MutPred

0.84

.;.;.;Loss of MoRF binding (P = 0.0284);.;Loss of MoRF binding (P = 0.0284);.;.;

MVP

0.87

MPC

0.12

ClinPred

0.12

GERP RS

4.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.42

gMVP

0.51

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