17-7670709-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000546.6(TP53):​c.1000G>A​(p.Gly334Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,528 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• 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 11 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-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-7670709-C-T is Pathogenic according to our data. Variant chr17-7670709-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 186086.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.1000G>A	p.Gly334Arg	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>A	p.Gly334Arg	missense_variant	Exon 10 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461528 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727038

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111798

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:1

Nov 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 334 of the TP53 protein (p.Gly334Arg). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with adrenocortical carcinoma (PMID: 25584008). A different variant (c.1000G>C) giving rise to the same protein effect has been observed in individual(s) with clinical features of Li-Fraumeni syndrome, including adrenocortical tumors, breast cancer, and hematological malignancies. However, c.1000G>C has also been observed in unaffected individuals, which is suggestive of reduced penetrance (PMID: 23580068, 24448499, 25452441, 25503501, 32675277; Invitae). Although the penetrance for each base change has yet to be established, evidence from the c.1000G>C variant suggests that c.1000G>A is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 186086). 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, 25584008, 29955864, 30224644, 32675277). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 22, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G334R variant (also known as c.1000G>A), located in coding exon 9 of the TP53 gene, results from a G to A substitution at nucleotide position 1000. The glycine at codon 334 is replaced by arginine, an amino acid with dissimilar properties. Residue G334 is the hinge residue between the alpha helix and beta sheet in the tetramerization domain of the p53 protein (Clore et al. Nat Struct Biol. 1995 Apr;2(4):321-33) and has been shown to be sensitive to substitution through in vitro analysis and predictive modeling (Kawaguchi et al. Oncogene 2005 Oct 20;24(46):6976-81; Higa et al. Genet Mol Biol.2009 Jul;32(3):626-33). This variant was detected in an individual with ovarian cancer (Kanchi et al. Nat Commun. 2014;5:3156) and an individual with Her2+ breast cancer who met Chompret criteria for Li-Fraumeni Syndrome (Rath et al. Breast Cancer Res Treat. 2013 May;139(1):193-8). However, yeast-based functional studies have shown that this variation has transactivation capability similar to wild type (Kato S et al.Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear. -

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	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;D;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;.;.;D;D;D
M_CAP	Pathogenic	0.71	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	0.64	T
PROVEAN	Pathogenic	-7.0	.;.;.;D;.;D;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;.;.;D;.;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;.;D;.;.
Vest4		0.89
MutPred		0.90		.;.;.;Gain of MoRF binding (P = 0.0278);.;Gain of MoRF binding (P = 0.0278);.;.;
MVP		1.0
MPC		0.41
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.3
Varity_R		0.98
gMVP		0.81
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs730882028; hg19: chr17-7574027;