17-7673770-T-G

Variant names:

• chr17-7673770-T-G
• rs1204379654
• NM_000546.6:c.850A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000546.6(TP53):​c.850A>C​(p.Thr284Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T284A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 1.29
• Publications: 80 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 42 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 30 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7673770-T-G is Pathogenic according to our data. Variant chr17-7673770-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1763670.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.850A>C	p.Thr284Pro	missense	Exon 8 of 11	NP_000537.3
	TP53	NM_001126112.3		c.850A>C	p.Thr284Pro	missense	Exon 8 of 11	NP_001119584.1
	TP53	NM_001407262.1		c.850A>C	p.Thr284Pro	missense	Exon 9 of 12	NP_001394191.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.850A>C	p.Thr284Pro	missense	Exon 8 of 11	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.850A>C	p.Thr284Pro	missense	Exon 8 of 11	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.733A>C	p.Thr245Pro	missense	Exon 7 of 10	ENSP00000478219.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 18, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T284P variant (also known as c.850A>C), located in coding exon 7 of the TP53 gene, results from an A to C substitution at nucleotide position 850. The threonine at codon 284 is replaced by proline, an amino acid with highly similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-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 indicate this alteration is deficient at growth suppression and has a dominant negative effect (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 not well conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

Li-Fraumeni syndrome Uncertain:1

Apr 27, 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: 1763670). 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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 284 of the TP53 protein (p.Thr284Pro).

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.50		Loss of phosphorylation at T284 (P = 0.0034)
MVP		0.98
MPC		0.42
ClinPred		0.99	D
GERP RS		3.9
PromoterAI		-0.030	Neutral
Varity_R		0.99
gMVP		0.73

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: rs1204379654; hg19: chr17-7577088; COSMIC: COSV52896079; COSMIC: COSV52896079;