rs794727846

Variant names:

• chr17-7674253-ATGTAGT-A
• rs794727846
• NM_000546.6:c.704_709delACTACA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM1 PM2 PM4 PP3 PP5

The NM_000546.6(TP53):​c.704_709delACTACA​(p.Asn235_Tyr236del) variant causes a disruptive inframe deletion change involving the alteration of a 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). ClinVar reports functional evidence for this variant: "SCV004933131: Functional studies indicate this variant impacts protein function [PMID:29979965]." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N235N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TP53 NM_000546.6 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 9.31
• Publications: 2 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 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004933131: Functional studies indicate this variant impacts protein function [PMID: 29979965].; SCV002662038: Based on the majority of available evidence to date, this variant is likely to be pathogenic. Cho Y et al., Science 1994 Jul; 265(5170):346-55).
• PM1: In a hotspot region, there are 49 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 32 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000546.6.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-7674253-ATGTAGT-A is Pathogenic according to our data. Variant chr17-7674253-ATGTAGT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198431.

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.704_709delACTACA	p.Asn235_Tyr236del	disruptive_inframe_deletion	Exon 7 of 11	NP_000537.3
	TP53	NM_001126112.3		c.704_709delACTACA	p.Asn235_Tyr236del	disruptive_inframe_deletion	Exon 7 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.704_709delACTACA	p.Asn235_Tyr236del	disruptive_inframe_deletion	Exon 8 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.704_709delACTACA	p.Asn235_Tyr236del	disruptive_inframe_deletion	Exon 7 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.704_709delACTACA	p.Asn235_Tyr236del	disruptive_inframe_deletion	Exon 7 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.587_592delACTACA	p.Asn196_Tyr197del	disruptive_inframe_deletion	Exon 6 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Hereditary cancer-predisposing syndrome (2)
1	1	-	Li-Fraumeni syndrome 1 (2)
1	-	-	Li-Fraumeni syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794727846; hg19: chr17-7577571; COSMIC: COSV52740030; COSMIC: COSV52740030;