17-7676587-T-C

Variant names:

• chr17-7676587-T-C
• rs786203938
• NM_000546.6:c.8A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000546.6(TP53):​c.8A>G​(p.Glu3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28418773).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.8A>G	p.Glu3Gly	missense_variant	Exon 2 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.8A>G	p.Glu3Gly	missense_variant	Exon 2 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461786 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727178

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 Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Jun 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E3G variant (also known as c.8A>G), located in coding exon 1 of the TP53 gene, results from an A to G substitution at nucleotide position 8. The glutamic acid at codon 3 is replaced by glycine, an amino acid with similar properties. This variant is reported to have functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). However, studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has no dominant negative effect (Giacomelli AO et al. Nat Genet, 2018 Oct;50:1381-1387). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome Uncertain:1

Oct 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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: 187706). 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 glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 3 of the TP53 protein (p.Glu3Gly). -

Li-Fraumeni syndrome 1 Uncertain:1

Jun 18, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T;T;D;.;.;.;D;.;T;T;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.88	D;D;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.4	.;.;M;M;M;M;M;.;.;.;.;.
PROVEAN	Benign	-0.67	N;N;N;.;N;N;N;.;N;N;.;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D;D;D;.;D;D;D;.;D;D;.;D
Sift4G	Uncertain	0.017	D;D;D;D;D;D;D;D;.;.;D;.
Polyphen		0.99	D;.;D;D;P;D;D;.;B;D;.;.
Vest4		0.39
MutPred		0.29		Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);
MVP		0.94
MPC		1.3
ClinPred		0.85	D
GERP RS		3.1
Varity_R		0.089
gMVP		0.39

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

Other links and lift over

dbSNP: rs786203938; hg19: chr17-7579905; COSMIC: COSV53377654; COSMIC: COSV53377654;