NM_000546.6:c.214_215delCCinsTG

Variant names:

• chr17-7676154-GG-CA
• rs730882014
• NM_000546.6:c.214_215delCCinsTG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.214_215delinsTG variant in TP53 is a deletion/insertion variant predicted to cause substitution of proline by cysteine at amino acid 72 (p.Pro72Cys). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as variant of uncertain clinical significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, PM2_Supporting. (Bayesian Points: -1; VCEP specifications version 2.2; 2/6/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000069/MONDO:0018875/009

• Frequency: GnomAD MNV: 𝑓 0.000012 Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:8 B:1
• Conservation: PhyloP100: 1.44
• Publications: 9 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 1 ACMG points.

• PM2: 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.214_215delCCinsTG	p.Pro72Cys	missense	N/A	NP_000537.3
	TP53	NM_001126112.3		c.214_215delCCinsTG	p.Pro72Cys	missense	N/A	NP_001119584.1
	TP53	NM_001407262.1		c.214_215delCCinsTG	p.Pro72Cys	missense	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.214_215delCCinsTG	p.Pro72Cys	missense	N/A	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.214_215delCCinsTG	p.Pro72Cys	missense	N/A	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.97_98delCCinsTG	p.Pro33Cys	missense	N/A	ENSP00000478219.1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

GnomAD MNV AF: 0.0000120 AC: 3 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	2	-	Li-Fraumeni syndrome (2)
-	2	-	Li-Fraumeni syndrome 1 (2)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	TP53-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4

Splicing

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

Other links and lift over

dbSNP: rs730882014; hg19: chr17-7579472; COSMIC: COSV105026609;