rs587782490

chr17-7676029-AGAAGCCCAGACG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM4 PP5_Moderate

The NM_000546.6(TP53):c.328_339del(p.Arg110_Phe113del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R110R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.47

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 6 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 16 uncertain in NM_000546.6
• PM4: Nonframeshift variant in NON repetitive region in NM_000546.6.
• PP5: Variant 17-7676029-AGAAGCCCAGACG-A is Pathogenic according to our data. Variant chr17-7676029-AGAAGCCCAGACG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142480.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.328_339del	p.Arg110_Phe113del	inframe_deletion	4/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.328_339del	p.Arg110_Phe113del	inframe_deletion	4/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2023

The c.328_339del12 variant (also known as p.R110_F113del) is located in coding exon 3 of the TP53 gene. This variant results from an in-frame deletion of 12 nucleotides (CGTCTGGGCTTC) at positions 328 to 339. This results in the in-frame deletion of 4 amino acids (RLGF) at codons 110 to 113. The amino acid positions 111 and 113 are well conserved, and amino acid positions 110 and 112 are not well conserved. Yeast-based functional assays shows that missense alterations at the deleted codons result primarily in a non-functional p53 protein (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). In addition, missense alterations in codon 110 have been identified a Li-Fraumeni family, and as germline alterations in a number of p53-related cancers, including early onset breast cancer and sarcoma (Mitchell G, PLoS ONE 2013 ; 8(7):e69026. Rath MG, Breast Cancer Res. Treat. 2013 May; 139(1):193-8. Masciari S, Genet. Med. 2011 Jul; 13(7):651-7. Rines RD, Carcinogenesis 1998 Jun; 19(6):979-84). Structural analysis indicates that this deletion exhibits structural perturbations to the DNA binding domain and would be pathogenic (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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: rs587782490; hg19: chr17-7579347;