rs876660749

Positions:

• chr17-7674862-AGGCGGCTCATAG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_000546.6(TP53):​c.657_668del​(p.Tyr220_Pro223del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 10.0

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) 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.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-7674862-AGGCGGCTCATAG-A is Pathogenic according to our data. Variant chr17-7674862-AGGCGGCTCATAG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 233946.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.657_668del	p.Tyr220_Pro223del	inframe_deletion	6/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.657_668del	p.Tyr220_Pro223del	inframe_deletion	6/11	1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 15, 2024

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2017

The c.657_668del12 variant (also known as p.Y220_P223del) is located in coding exon 5 of the TP53 gene. This variant results from an in-frame CTATGAGCCGCC deletion of between nucleotide positions 657 and 668. While this exact alteration has not been reported in the literature, a nearby alteration, c.643_660del18 (p.S215_Y220del), that overlaps the c.657_668del12 variant by 3 nucleotides has been reported in a woman diagnosed with bilateral breast cancer at age 40 from a cohort of 240 women with early-onset breast cancer or their affected relatives from four breast disease clinical centers in China. This study also looked at the functional significance of the c.643_660del18 variant in vitro and found that it had lower transcriptional activity and lower ability to induce cell apoptosis versus wild-type p53 (Cao AY et al, Breast Cancer Res. Treat. 2010 Jan; 119(2):295-303). The c.657_668del12 variant is located in the core DNA-binding domain of the TP53 gene wherein roughly 97% of p53 mutations are clustered, 75% of which are missense mutations (Kato S et al, Proc. Natl. Acad. Sci. U.S.A. 2003 Jul; 100(14):8424-9). These amino acid positions are generally well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876660749; hg19: chr17-7578180;