rs1131691033

Variant names:

• chr17-7673533-AC-A
• rs1131691033
• NM_000546.6:c.993+1delG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2_Supporting PS4_Supporting PVS1_Strong PP1

This summary comes from the ClinGen Evidence Repository: The NM_000546.6:c.993+1del is a deletion of a single G nucleotide within the canonical donor site of exon 9 of TP53. Through exon 9 skipping, the variant is observed in an RT-PCR assay to produce multiple aberrant transcripts encoding frameshift alterations predicted to induce nonsense-mediated decay. Since the assay does not fully account for leakiness, code weight downgraded to Strong (PVS1_Strong (RNA); PMID:10980596). This variant has been reported in 1 proband meeting Classic LFS criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID:10980596). This variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; PMID:10980596). This variant is absent from gnomAD v4.1.0 (PM2_Supporting).. In summary, this variant meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PVS1_Strong(RNA), PS4_Supporting, PP1, PM2_Supporting (Bayesian Points: 7; VCEP specifications version 2.0; 7/24/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA645369685/MONDO:0018875/009

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 splice_donor, intron
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 2.33
• 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: 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

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.993+1delG		splice_donor intron	N/A	NP_000537.3
	TP53	NM_001126112.3		c.993+1delG		splice_donor intron	N/A	NP_001119584.1
	TP53	NM_001407262.1		c.993+1delG		splice_donor intron	N/A	NP_001394191.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.993+1delG		splice_donor intron	N/A	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.993+1delG		splice_donor intron	N/A	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.876+1delG		splice_donor intron	N/A	ENSP00000478219.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Li-Fraumeni syndrome (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 2

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

Other links and lift over

dbSNP: rs1131691033; hg19: chr17-7576851; COSMIC: COSV99391417;