rs587782391

Positions:

chr17-7673713-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. BP4PM2_SupportingBS3

This summary comes from the ClinGen Evidence Repository: This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). Transactivation assays show 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 summary, TP53 c.907A>G (p.Ser303Gly) 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, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000491/MONDO:0007903/009

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TP53
ENST00000269305.9 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:4B:2

Conservation

PhyloP100: 0.779

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.

PM2

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

BP4

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.907A>G	p.Ser303Gly	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.907A>G	p.Ser303Gly	missense_variant	8/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign: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	Jan 03, 2024	This missense variant replaces serine with glycine at codon 303 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 was neutral in yeast transcriptional transactivation studies and human cell growth suppression assays (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has not been identified 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	Apr 22, 2023	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. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 142332). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 303 of the TP53 protein (p.Ser303Gly). -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 20, 2023	This missense variant replaces serine with glycine at codon 303 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 was neutral in yeast transcriptional transactivation studies and human cell growth suppression assays (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has not been identified 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	Jul 07, 2020	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

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 23, 2018

- -

Li-Fraumeni syndrome 1

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen TP53 Variant Curation Expert Panel, ClinGen

May 07, 2021

This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). Transactivation assays show 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 summary, TP53 c.907A>G (p.Ser303Gly) 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, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Benign

0.58

DEOGEN2

Benign

0.0051

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

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.83

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

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.22

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

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

MutationTaster

Benign

0.55

D;D;D;D;D;D

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.49

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

REVEL

Uncertain

0.37

Sift

Benign

0.40

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

Sift4G

Benign

0.39

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

Polyphen

0.024, 0.020, 0.96

.;.;.;.;.;.;.;.;B;.;B;D;B;.;.;B;.;.;.

Vest4

0.21

MutPred

0.23

Loss of glycosylation at S303 (P = 0.0092);.;.;.;.;.;.;.;Loss of glycosylation at S303 (P = 0.0092);.;Loss of glycosylation at S303 (P = 0.0092);Loss of glycosylation at S303 (P = 0.0092);Loss of glycosylation at S303 (P = 0.0092);.;.;Loss of glycosylation at S303 (P = 0.0092);.;.;.;

MVP

0.87

MPC

0.19

ClinPred

0.21

GERP RS

5.3

Varity_R

0.11

gMVP

0.44

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