rs1555524354

Positions:

• chr17-7670625-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000546.6(TP53):​c.1083del​(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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G361G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TP53 NM_000546.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.327

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 Pathogenic. Variant got 12 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. Fraction of 0.0838 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7670625-TC-T is Pathogenic according to our data. Variant chr17-7670625-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 549856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.1083del	p.Ser362AlafsTer8	frameshift_variant	10/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.1083del	p.Ser362AlafsTer8	frameshift_variant	10/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461010 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726826

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bone marrow failure syndrome 5 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	May 18, 2020	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The heterozygous p.Ser362AlafsTer8 variant in TP53 was identified by our study in one individual with bone marrow failure syndrome 5. The p.Ser362AlafsTer8 variant in TP53 has been previously reported in 2 unrelated individuals with bone marrow failure syndrome 5 (PMID: 30146126, PMID: 35362179). This variant was found to be de novo in one individual with confirmed maternity and paternity (PMID: 30146126) and is assumed de novo in one individual but maternity and paternity have not been confirmed (PMID: 35362179). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (ID: 549856) and has been interpreted as pathogenic by the Hirosaki University Graduate School of Medicine Department of Pediatrics and OMIM. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Ser362AlafsTer8 variant may impact protein function (PMID: 30146126). However, these types of assays may not accurately represent biological function. Animal models in zebrafish have shown that this variant causes bone marrow failure syndrome 5 (PMID: 30146126). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 362 and leads to a premature termination codon 8 amino acids downstream. This termination codon occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. It is of note that loss of function of the TP53 in autosomal dominant bone marrow failure syndrome 5 has not yet been established based on the criteria laid out in Tayoun et al., 2018 (PMID: 30192042), and based on the published literature, this variant appears to cause disease via a gain of function mechanism (PMID: 30146126). In summary, this variant meets criteria to be classified as pathogenic for bone marrow failure syndrome 5. ACMG/AMP Criteria applied: PS2, PS3, PS4_Supporting, PM2_Supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frame shift (c.1083del) variant has been reported previously in heterozygous state in patients affected with Bone marrow failure syndrome 5 (Toki et. al., 2018; Hamard et. al., 2013). The p.Ser362AlafsTer8 variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. Experimental studies have demonstrate that the CTD-truncation mutations of TP53 cause a novel inherited bone marrow failure syndrome (Toki et. al., 2018). This variant causes a frameshift starting with codon Serine 362, changes this amino acid to Alanine residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Ser362AlafsTer8. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. Though classified as Pathogenic, Sanger confirmation is required to confirm presence of variant due to low depth -

Diamond-Blackfan anemia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Pediatrics, Hirosaki University Graduate School of Medicine

May 14, 2018

The heterozygous protein-truncating mutations in TP53 (c.1083delG, 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

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: rs1555524354; hg19: chr17-7573943;