chr17-7676047-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2

The NM_000546.6(TP53):c.322G>C(p.Gly108Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,460,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 0.902

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 0 ACMG points.

PM1

In a region_of_interest Required for interaction with ZNF385A (size 200) in uniprot entity P53_HUMAN there are 58 pathogenic changes around while only 4 benign (94%) in NM_000546.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

BS2

High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.322G>C	p.Gly108Arg	missense_variant	Exon 4 of 11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.322G>C	p.Gly108Arg	missense_variant	Exon 4 of 11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1460150

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726350

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Jun 18, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 03, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with arginie at codon 801 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have reported partial function in a yeast based transactivation assay (PMID: 12826609), functional in a human cell growth suppression assay (PMID: 30224644), and inconclusive in a human cell proliferation assay (PMID: 29979965). 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. -

Jun 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G108R variant (also known as c.322G>C), located in coding exon 3 of the TP53 gene, results from a G to C substitution at nucleotide position 322. The glycine at codon 108 is replaced by arginine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Li-Fraumeni syndrome

Uncertain:2

May 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 458535). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 108 of the TP53 protein (p.Gly108Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) did not meet the statistical confidence thresholds required to predict the impact of this variant on TP53 function. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965). 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. -

Oct 11, 2019

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Data included in classification: UK family 1: proband with 3 primaries (breast cancer at 30 and 35, glioblastoma at 33). (PS4_sup) Variant absent from gnomAD controls (PM2_sup). Data not included in classification: Conflicting in silico class 0 on AlignGVGD and BayesDEL score 0.22 Functional studies: Kato et al, 2003 (PMID 12826609) Partially functional (between 20-75% activity) Giacomelli et al 2018 (PMID 30224644) - LOF only (unclassified) Other changes at codon suggested pathogenic (Gly108Asp), but only one reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886078/pdf/ddx106.pdf Parental samples not yet obtained, but have been requested to confirm if de novo or inherited. -

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

- -

Adrenocortical carcinoma, hereditary

Uncertain:1

Jul 10, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast

Uncertain:1

Neuberg Centre For Genomic Medicine, NCGM

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

0.32

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

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

Eigen

Benign

0.069

Eigen_PC

Benign

-0.060

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.91

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

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

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.4

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

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.023

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

Polyphen

1.0

D;.;.;P;.;P;D;P;.;.;P;.;.;P;.;.

Vest4

0.56

MutPred

0.80

Gain of MoRF binding (P = 0.0099);Gain of MoRF binding (P = 0.0099);.;Gain of MoRF binding (P = 0.0099);.;Gain of MoRF binding (P = 0.0099);Gain of MoRF binding (P = 0.0099);Gain of MoRF binding (P = 0.0099);.;.;Gain of MoRF binding (P = 0.0099);.;Gain of MoRF binding (P = 0.0099);Gain of MoRF binding (P = 0.0099);Gain of MoRF binding (P = 0.0099);Gain of MoRF binding (P = 0.0099);

MVP

0.97

MPC

1.8

ClinPred

0.92

GERP RS

2.8

Varity_R

0.82

gMVP

0.63

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