17-7673821-G-A

Variant names:

• chr17-7673821-G-A
• rs55832599
• NM_000546.6:c.799C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):​c.799C>T​(p.Arg267Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,072 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000185257: Additional functional assays conducted in human tumor cell lines demonstrated a lack of transactivation activity, deficient DNA binding, and an inability to suppress cell growth in response to DNA damaging agents (Wang B et al. Cell Death Differ. 2014 Apr" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R267P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24 O:2
• Conservation: PhyloP100: 2.31
• Publications: 162 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 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000185257: Additional functional assays conducted in human tumor cell lines demonstrated a lack of transactivation activity, deficient DNA binding, and an inability to suppress cell growth in response to DNA damaging agents (Wang B et al. Cell Death Differ. 2014 Apr; 21(4):521-32; Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8).; SCV000686775: Functional studies have shown the mutant protein to be defective in transactivation, apoptosis induction, and cell growth control activity (PMID: 9627118, 12019170, 12826609, 24076587, 29979965).; SCV005901778: "A second assay based on in vitro growth assays in H1299 human cells from Kotler 2018 shows loss of function (RFS=-0.64, PS3)." PMID: 29979965; SCV000491277: Published functional studies demonstrate a damaging effect: non-functional or decreased transactivation, and decreased or wildtype-like growth suppression activity (PMID: 9627118, 12826609, 16861262, 21232794, 25831048, 30224644, 29979965).; SCV004221374: Functional studies have found this variant impairs transcriptional activity, DNA binding, and apoptosis (PMID: 24076587 (2014), 16861262 (2007)).; SCV000629873: Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 24076587).; SCV001429670: Functional data: Non-functional on Kato et al, 2003(PMID: 12826609); impaired function on Fulci et al, 2002: PMID: 12019170), Wang et al, 2013 (PMID: 24076587), Perez et al, 2016 (PMID: 27022024) (PS3_strong).; SCV002598661: Multiple publications have reported that this variant impairs the normal activity of the protein (examples: Wang_2014 and Dearth_2006).; SCV004823766: Functional studies have shown the mutant protein to be defective in transactivation, apoptosis induction, and cell growth control activity (PMID: 9627118, 12019170, 12826609, 24076587, 29979965).; SCV004931961: Functional studies indicate this variant impacts protein function [PMID: 24076587, 27022024, 29979965].
• PM1: In a hotspot region, there are 41 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 32 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 chr17-7673820-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 428867.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-7673821-G-A is Pathogenic according to our data. Variant chr17-7673821-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 141764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.799C>T	p.Arg267Trp	missense	Exon 8 of 11	NP_000537.3
	TP53	NM_001126112.3		c.799C>T	p.Arg267Trp	missense	Exon 8 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.799C>T	p.Arg267Trp	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.799C>T	p.Arg267Trp	missense	Exon 8 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.799C>T	p.Arg267Trp	missense	Exon 8 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.682C>T	p.Arg228Trp	missense	Exon 7 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 248996 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461072 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726772

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111640

Other (OTH) AF: 0.0000166 AC: 1 AN: 60362

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000151 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Li-Fraumeni syndrome (5)
5	-	-	not provided (5)
4	-	-	Hereditary cancer-predisposing syndrome (4)
2	-	-	Adrenocortical carcinoma, hereditary (2)
2	-	-	Li-Fraumeni syndrome 1 (2)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0585442:Bone osteosarcoma;C0699790:Carcinoma of colon;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7 (1)
1	-	-	Familial cancer of breast (1)
1	-	-	Familial cancer of breast;C1835398:Li-Fraumeni syndrome 1 (1)
1	-	-	Lip and oral cavity carcinoma (1)
1	-	-	TP53-related disorder (1)
-	-	-	Medulloblastoma WNT activated (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.98
MutPred		0.91		Loss of disorder (P = 0.0012)
MVP		0.99
MPC		0.28
ClinPred		1.0	D
GERP RS		4.2
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.87
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs55832599; hg19: chr17-7577139; COSMIC: COSV52678166; COSMIC: COSV52678166;