Submissions for variant NM_000546.6(TP53):c.1083del (p.Ser362fs)

dbSNP: rs1555524354

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000714961	SCV003761378	pathogenic	Bone marrow failure syndrome 5	2023-01-25	criteria provided, single submitter	curation	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).
Neuberg Centre For Genomic Medicine, NCGM	RCV000714961	SCV004047084	pathogenic	Bone marrow failure syndrome 5		criteria provided, single submitter	clinical testing	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
Department of Pediatrics, Hirosaki University Graduate School of Medicine	RCV000677307	SCV000786665	pathogenic	Diamond-Blackfan anemia	2018-05-14	no assertion criteria provided	research	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.
OMIM	RCV000714961	SCV000845726	pathogenic	Bone marrow failure syndrome 5	2020-05-18	no assertion criteria provided	literature only