chr17-7673784-C-T

Variant names:

• chr17-7673784-C-T
• rs1064793881
• NM_000546.6:c.836G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM1 PM2 PP3_Strong PP5

The NM_000546.6(TP53):​c.836G>A​(p.Gly279Glu) 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000567266: "Published functional studies demonstrate a damaging effect: non-functional transactivation, lack of growth suppression activity, and inability to induce apoptosis." PMID:12826609, 29979965, 30224644, 16861262, 30166522, 11896595, 11429700, 12909720, 16508005, 11313981; SCV000581126: "A number of functional assays in both yeast and mammalian cells have shown this alteration to be devoid of transactivation activity, deficient in the induction of apoptosis, and unable to suppress cell growth after UV irradiation (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Menendez D et al. Mol. Cell. Biol. 2006 Mar; 26(6):2297-308; Inga A et al. Oncogene. 2001 Jan; 20(4):501-13; Rokudai Set al. J Biol Chem. 2009 Jan 2;284(1):237-44; Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat Genet. 2018 10;50:1381-1387)."; SCV004932899: Functional studies indicate this variant impacts protein function [PMID:16508005].". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G279W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:2
• Conservation: PhyloP100: 6.16
• Publications: 111 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), 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 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000567266: "Published functional studies demonstrate a damaging effect: non-functional transactivation, lack of growth suppression activity, and inability to induce apoptosis." PMID: 12826609, 29979965, 30224644, 16861262, 30166522, 11896595, 11429700, 12909720, 16508005, 11313981; SCV000581126: "A number of functional assays in both yeast and mammalian cells have shown this alteration to be devoid of transactivation activity, deficient in the induction of apoptosis, and unable to suppress cell growth after UV irradiation (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Menendez D et al. Mol. Cell. Biol. 2006 Mar; 26(6):2297-308; Inga A et al. Oncogene. 2001 Jan; 20(4):501-13; Rokudai Set al. J Biol Chem. 2009 Jan 2;284(1):237-44; Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat Genet. 2018 10;50:1381-1387)."; SCV004932899: Functional studies indicate this variant impacts protein function [PMID: 16508005].
• PM1: In a hotspot region, there are 67 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 26 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 17-7673784-C-T is Pathogenic according to our data. Variant chr17-7673784-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 419454.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.836G>A	p.Gly279Glu	missense	Exon 8 of 11	NP_000537.3
	TP53	NM_001126112.3		c.836G>A	p.Gly279Glu	missense	Exon 8 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.836G>A	p.Gly279Glu	missense	Exon 9 of 12	NP_001394191.1	K7PPA8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.836G>A	p.Gly279Glu	missense	Exon 8 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.836G>A	p.Gly279Glu	missense	Exon 8 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.719G>A	p.Gly240Glu	missense	Exon 7 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	Li-Fraumeni syndrome 1 (2)
2	-	-	not provided (2)
-	1	-	Li-Fraumeni syndrome (1)
-	1	-	not specified (1)
1	-	-	Ovarian neoplasm (1)
1	-	-	Squamous cell carcinoma of the head and neck (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.84		Gain of solvent accessibility (P = 0.0026)
MVP		0.95
MPC		0.43
ClinPred		1.0	D
GERP RS		4.2
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.79
Mutation Taster		=0/100	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: rs1064793881; hg19: chr17-7577102; COSMIC: COSV52677880; COSMIC: COSV52677880;