17-7675999-A-T

Position:

chr17-7675999-A-T

Variant summary

Our verdict is Uncertain significance. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS3

This summary comes from the ClinGen Evidence Repository: Transactivation assays show retained 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). This variant has a BayesDel score greater than or equal to 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). In summary, the clinical significance of TP53 c.370T>A (p.Cys124Ser) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000138/MONDO:0007903/009

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4B:1

Conservation

PhyloP100: 5.75

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 Uncertain_significance. Variant got -2 ACMG points.

PP3

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.370T>A	p.Cys124Ser	missense_variant	4/11	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.370T>A	p.Cys124Ser	missense_variant	4/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250848

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.00000137

AC:

AN:

1459964

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726278

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 27, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 06, 2020	- -

Li-Fraumeni syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 03, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 124 of the TP53 protein (p.Cys124Ser). This variant is present in population databases (rs730881997, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 182926). 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, 25584637, 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. -

Li-Fraumeni syndrome 1

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Jan 10, 2022

Transactivation assays show retained 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). This variant has a BayesDel score greater than or equal to 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). In summary, the clinical significance of TP53 c.370T>A (p.Cys124Ser) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, PP3_Moderate. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2015

This variant is denoted TP53 c.370T>A at the cDNA level, p.Cys124Ser (C124S) at the protein level, and results in the change of a Cysteine to a Serine (TGC>AGC). This variant has been studied functionally, but with varied results regarding its effect on p53 function (Buzek 2002, Baroni 2004, Stoner 2009, Kim 2010). This variant has also been reported as having functional transactivation activity in the International Agency for Research on Cancer (IARC) TP53 database based on functional assays by Kato et al (2003). TP53 Cys124Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Cys124Ser occurs at a position that is conserved in mammals and is located in the DNA binding domain and in a region known to interact with multiple proteins (Uniprot). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether TP53 Cys124Ser is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.50

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

Eigen

Benign

0.086

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.63

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

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.80

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.4

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.6

N;N;.;N;.;.;N;N;.;.;N;.;N;.;D

REVEL

Pathogenic

0.72

Sift

Benign

0.42

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

Sift4G

Benign

0.74

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

Polyphen

0.15

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

Vest4

0.21

MutPred

0.79

Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);.;Gain of disorder (P = 0.0063);.;Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);.;.;Gain of disorder (P = 0.0063);.;Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);

MVP

0.86

MPC

1.8

ClinPred

0.40

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.62

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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