NM_000546.6:c.328_339delCGTCTGGGCTTC

Variant names:

• chr17-7676029-AGAAGCCCAGACG-A
• rs587782490
• NM_000546.6:c.328_339delCGTCTGGGCTTC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PM4 PP5_Very_Strong

The NM_000546.6(TP53):​c.328_339delCGTCTGGGCTTC​(p.Arg110_Phe113del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000186637: Yeast-based functional assays shows that missense alterations at the deleted codons result primarily in a non-functional p53 protein (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R110R) has been classified as Likely benign. The gene TP53 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.47
• 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

Specifications for TP53 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000186637: Yeast-based functional assays shows that missense alterations at the deleted codons result primarily in a non-functional p53 protein (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9).; SCV005625954: "In addition, yeast functional studies showed that missense variants at the deleted codons 110-113 result in partial loss of p53 protein function (PMID: 12826609 (2003))."
• PM1: In a hotspot region, there are 24 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 32 uncertain in NM_000546.6
• PM4: Nonframeshift variant in NON repetitive region in NM_000546.6.
• PP5: Variant 17-7676029-AGAAGCCCAGACG-A is Pathogenic according to our data. Variant chr17-7676029-AGAAGCCCAGACG-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 142480.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.328_339delCGTCTGGGCTTC	p.Arg110_Phe113del	conservative_inframe_deletion	Exon 4 of 11	NP_000537.3
	TP53	NM_001126112.3		c.328_339delCGTCTGGGCTTC	p.Arg110_Phe113del	conservative_inframe_deletion	Exon 4 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.328_339delCGTCTGGGCTTC	p.Arg110_Phe113del	conservative_inframe_deletion	Exon 5 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.328_339delCGTCTGGGCTTC	p.Arg110_Phe113del	conservative_inframe_deletion	Exon 4 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.328_339delCGTCTGGGCTTC	p.Arg110_Phe113del	conservative_inframe_deletion	Exon 4 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.211_222delCGTCTGGGCTTC	p.Arg71_Phe74del	conservative_inframe_deletion	Exon 3 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587782490; hg19: chr17-7579347; COSMIC: COSV109410046;