17-7669671-C-G

Position:

chr17-7669671-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BS2BS3

This summary comes from the ClinGen Evidence Repository: The NM_000546.6:c.1120G>C variant in TP53 is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 374 (p.Gly374Arg). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2, Internal lab contributors: SCV000273745.6). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (PMIDs: 12826609, 29979965, 30224644) (BS3). Computational predictor scores (BayesDel = -0.0546; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BP4_moderate. (Bayesian Points: -10; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000677/MONDO:0018875/009

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TP53
ENST00000269305.9 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:4B:3

Conservation

PhyloP100: 1.29

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 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.1120G>C	p.Gly374Arg	missense_variant	11/11	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.1120G>C	p.Gly374Arg	missense_variant	11/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251338

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727198

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.0000725

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:4Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 374 of the TP53 protein (p.Gly374Arg). This variant is present in population databases (rs587781858, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 31321604). ClinVar contains an entry for this variant (Variation ID: 230269). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 14, 2024	This missense variant replaces glycine with arginine at codon 374 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have shown that this variant behaved as wild-type in yeast transcriptional transactivation studies and human cell growth suppression assays (PMID: 12826609, 30224644). This variant has been reported in an individual affected with sporadic breast cancer (PMID: 31321604). This variant has been identified in 2/282716 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. -
Benign, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Aug 05, 2024	The NM_000546.6:c.1120G>C variant in TP53 is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 374 (p.Gly374Arg). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2, Internal lab contributors: SCV000273745.6). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (PMIDs: 12826609, 29979965, 30224644) (BS3). Computational predictor scores (BayesDel = -0.0546; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BP4_moderate. (Bayesian Points: -10; VCEP specifications version 2.0; 7/24/2024) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 30, 2018	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	Mar 08, 2023	This missense variant replaces glycine with arginine at codon 374 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant does not impact TP53 protein function (PMID: 12826609, 30224644). This variant has been reported in an individual affected with sporadic breast cancer (PMID: 31321604). This variant has been identified in 2/282716 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2017

This variant is denoted TP53 c.1120G>C at the cDNA level, p.Gly374Arg (G374R) at the protein level, and results in the change of a Glycine to an Arginine (GGT>CGT). This variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Gly374Arg was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Gly374Arg occurs at a position that is not conserved and is located in the C-terminal regulatory domain and a nuclear localization signal (Shaulsky 1990, Bode 2004, Pessoa 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether TP53 Gly374Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

TP53-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.59

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

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.82

T;T;.;.;.;T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.13

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

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

1.4

.;.;.;L;.;L;.;.

MutationTaster

Benign

0.96

D;D;D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.1

.;.;.;N;.;N;.;.

REVEL

Uncertain

0.37

Sift

Benign

0.047

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

Sift4G

Uncertain

0.051

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

Polyphen

0.0050

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

Vest4

0.23

MutPred

0.26

.;.;.;Gain of solvent accessibility (P = 0.0037);.;Gain of solvent accessibility (P = 0.0037);.;.;

MVP

0.87

MPC

2.1

ClinPred

0.17

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.32

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