rs1555524370

Variant names:

• chr17-7670631-CT-C
• rs1555524370
• NM_000546.6:c.1077delA

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000546.6(TP53):​c.1077delA​(p.Ser362AlafsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P359P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.823
• Publications: 0 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7670631-CT-C is Pathogenic according to our data. Variant chr17-7670631-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 549855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.1077delA	p.Ser362AlafsTer8	frameshift_variant	Exon 10 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.1077delA	p.Ser362AlafsTer8	frameshift_variant	Exon 10 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bone marrow failure syndrome 5 Pathogenic:2

-

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 28, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1077delA variant, located in coding exon 9 of the TP53 gene, results from a deletion of one nucleotide at nucleotide position 1077, causing a translational frameshift with a predicted alternate stop codon (p.S362Afs*8). This alteration occurs at the 3' terminus of theTP53 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 8.1% of the protein. The exact functional effect of this alteration is unknown. This variant has been reported as de novo in two patients with features consistent with TP53-related bone marrow failure, and functional studies indicate this variant possesses enhanced p53 activity and impaired erythroid differentiation (Toki T et al. Am J Hum Genet, 2018 Sep;103:440-447; Fedorova D et al. Pediatr Blood Cancer, 2022 Apr;69:e29558). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is likely pathogenic for TP53-related bone marrow failure; however, the association of this alteration with Li-Fraumeni syndrome is unknown. -

Diamond-Blackfan anemia Pathogenic:1

May 14, 2018

Department of Pediatrics, Hirosaki University Graduate School of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The heterozygous protein-truncating mutations in TP53 (c.1077delA, p.Ser362AlafsX8) was detected in a patient presented with congenital hypoplastic anemia, hypogammaglobulinemia, growth retardation, microcephally and mental retardation. The variant resulted in the loss of 32 residues from the C-terminal domain (CTD). Luciferase assay using the promoter of CDKN1A showed the p53 mutant had augmented transcriptional activities. When expressed in zebrafish and human-induced pluripotent stem cells, we observed impaired erythrocyte production. The patient shared several phenotypes with the knock-in mice expressing CTD-truncated p53, including bone marrow failure, microcephaly and severe growth retardation (Simeonova 2013, Hamard 2013). These findings demonstrate that the CTD-truncation mutations of TP53 cause a novel inherited bone marrow failure syndrome. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.82
Mutation Taster		=15/185	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555524370; hg19: chr17-7573949;