rs786204061

Variant names:

• chr17-7673771-G-GCGCCGGTCTCTCCCAGGA
• rs786204061
• NM_000546.6:c.831_848dupTCCTGGGAGAGACCGGCG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM4

The NM_000546.6(TP53):​c.831_848dupTCCTGGGAGAGACCGGCG​(p.Arg283_Thr284insProGlyArgAspArgArg) variant causes a disruptive inframe insertion change involving the alteration of a non-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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R283R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.18
• Publications: 1 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 4 ACMG points.

• PM1: In a hotspot region, there are 46 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 27 uncertain in NM_000546.6
• PM4: Nonframeshift variant in NON repetitive region in NM_000546.6.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.831_848dupTCCTGGGAGAGACCGGCG	p.Arg283_Thr284insProGlyArgAspArgArg	disruptive_inframe_insertion	Exon 8 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.831_848dupTCCTGGGAGAGACCGGCG	p.Arg283_Thr284insProGlyArgAspArgArg	disruptive_inframe_insertion	Exon 8 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Sep 16, 2014

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this is a novel, in-frame duplication with uncertain impact on protein function. While this region of TP53 is important for DNA binding, the evidence is insufficient at this time to prove that this sequence change affects protein function or causes disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change inserts 18 nucleotides in exon 8 of the TP53 mRNA (c.831_848dupTCCTGGGAGAGACCGGCG). This leads to the insertion of 6 amino acid residues in the TP53 protein (p.Pro278_Arg283dup), but otherwise preserves the integrity of the reading frame. This sequence change has not been published in the literature and is not present in population databases. The 6 duplicated amino acid residues Pro278-Arg283 fall in the DNA binding domain of the TP53 protein (amino acids 102-292) (PMID: 8276238). Several missense substitutions at these six codons have been reported in affected patients (PMID: 10864200, 11370630, 15173255, 8688334) and have been shown experimentally to disrupt TP53 protein function (PMID: 17606709, 21343334). -

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.831_848dup18 variant (also known as p.P278_R283dup), located in coding exon 7 of the TP53 gene, results from an in-frame duplication of 18 nucleotides at nucleotide positions 831 to 848. This results in the duplication of 6 extra residues (PGRDRR) between codons 278 and 283. This amino acid region is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2

Splicing

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

Other links and lift over

dbSNP: rs786204061; hg19: chr17-7577089;