rs587782270

Positions:

• chr17-7676387-CGTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PM4_Supporting

The NM_000546.6(TP53):​c.88_90del​(p.Asn30del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. N30N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP53 NM_000546.6 inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel U:7
• Conservation: PhyloP100: 0.549

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 13 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. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.88_90del	p.Asn30del	inframe_deletion	3/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.88_90del	p.Asn30del	inframe_deletion	3/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249510 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135562

Gnomad AFR exome AF: 0.0000631

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461644 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 22, 2023	The c.88_90delAAC variant (also known as p.N30del) is located in coding exon 2 of the TP53 gene. This variant results from an in-frame AAC deletion at nucleotide positions 88 to 90. This results in the in-frame deletion of an asparagine at codon 30. This alteration has been reported in a next generation sequencing (NGS) validation study of individuals undergoing testing for hereditary cancer (Chong HK et al. PLoS ONE. 2014 May;9:e97408). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was not identified in 87 patients with CS or BRRS and was reported in a cohort of 3476 cancer patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). The deleted amino acid is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 03, 2023	This variant causes an in-frame deletion of one amino acid at exon 3 of the TP53 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual undergoing clinical testing for hereditary cancer (PMID: 24830819). This variant has been identified in 1/249510 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

This variant, c.88_90del, results in the deletion of 1 amino acid(s) of the TP53 protein (p.Asn30del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587782270, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 142158). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 09, 2017

The p.Asn30del variant in TP53 has been reported as a germline variant in 1 indi vidual who underwent clinical testing for hereditary cancer, who also carried a pathogenic variant in the BRCA2 gene (Chong 2014), and has also been reported in ClinVar (Variation ID 142158). It has also been identified in 1/64924 of Europe an chromosomes and 1/9660 of African chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs587782270). This variant is a deletion of 1 amino acid at position 30 and is not predicted to alter the prot ein reading-frame. It is unclear if this deletion will impact the protein. In su mmary, the clinical significance of the p.Asn30del variant is uncertain. -

Li-Fraumeni syndrome 1 Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Apr 30, 2021

This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2; internal laboratory contributor). This variant has been reported in 2 probands meeting Chompret criteria (PS4_Supporting; internal laboratory contributors). In summary, the clinical significance of TP53 c.85_87AAC[1] (p.Asn30del) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS4_Supporting, BS2. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 08, 2023

In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter protein structure/function; Observed in individuals with renal cancer (PMID: 29684080); This variant is associated with the following publications: (PMID: 24830819, 30886117, 15510160, 29684080) -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 19, 2023

. According to the ClinGen ACMG TP53 v1.4.0 criteria we chose these criteria: PS4 (supporting pathogenic): This variant has been reported in 2 probands meeting Chompret criteria (PS4_Supporting; ClinGen TP53 Variant Curation Expert Panel), BS2 (supporting benign): This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2; ClinGen TP53 Variant Curation Expert Panel). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587782270; hg19: chr17-7579705;