rs730882028

Variant names:

• chr17-7670709-C-A
• rs730882028
• NM_000546.6:c.1000G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7670709-C-A
• chr17-7670709-C-G
• chr17-7670709-C-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):​c.1000G>T​(p.Gly334Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G334V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.94
• Publications: 88 publications found

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 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 20 benign, 25 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7670709-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 186086.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-7670709-C-A is Pathogenic according to our data. Variant chr17-7670709-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 428876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.1000G>T	p.Gly334Trp	missense_variant	Exon 10 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.1000G>T	p.Gly334Trp	missense_variant	Exon 10 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Oct 05, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with tryptophan at codon 334 in the tetramerization domain of the TP53 protein and is located 7 nucleotides from the intron 9 splice acceptor site. This variant alters the conserved glycine residue that connects a short beta-strand (Glu326-Arg333) and an alpha-helix (Arg335-Gly356) of each subunit of the tetramer by facilitating a sharp turn (PMID: 20516128, 26572807). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies performed in yeast assays and ex vivo cultured cells have shown that this variant has largely neutral effect on the tetramer formation and transactivation function of the TP53 protein (PMID: 12826609, 16007150, 19454241) and does not exhibit dominant negative effect or loss of TP53 function in a human cell growth suppression assay (PMID: 30224644). This variant has been observed to segregate with breast cancer, glioblastoma brain cancer, esophageal and rectal cancer in a family affected with Li-Fraumeni syndrome (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Gly334Arg, has been observed in multiple families affected with Li-Fraumeni syndrome meeting Chompret criteria (PMID: 23580068, 25503501, 25584008, 32675277; ClinVar variation ID: 182969) with reported incomplete penetrance (PMID: 25584008, 32675277), indicating that glycine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Aug 13, 2013

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

​The p.G334W variant (also known as c.1000G>T) is located in coding exon 9 of the TP53 gene. This alteration results from a G to T substitution at nucleotide position 1000. The glycine at codon 334 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant was detected in one Korean individual's non-small cell lung cancer tumor sample along with another TP53 mutation (Lee et al. J Korean Med Sci. 2010. 25:698-705). The p.G334W alteration is located in the tetramerization domain of the protein which is critical in tumor suppressor activity. Another alteration at codon 334 (p.G334V) showed lower DNA binding activity and transactivation ability in thermal stability studies (Kamada et al. J Biological Chem. 2011 Jan; 286(1):252-258). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome 1 Pathogenic:1

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;D;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.;.;.;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.4	.;.;.;M;.;M;.;.
PhyloP100		6.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.0	.;.;.;D;.;D;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;.;.;D;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;.;D;.;.
Vest4		0.92
MutPred		0.89		.;.;.;Gain of MoRF binding (P = 0.0248);.;Gain of MoRF binding (P = 0.0248);.;.;
MVP		1.0
MPC		0.41
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.81
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs730882028; hg19: chr17-7574027; COSMIC: COSV52820679; COSMIC: COSV52820679;