Submissions for variant NM_000051.4(ATM):c.4632_4635del (p.Lys1543_Tyr1544insTer)

dbSNP: rs1064794236

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481245	SCV000568324	pathogenic	not provided	2018-01-04	criteria provided, single submitter	clinical testing	This deletion of four nucleotides is denoted ATM c.4632_4635delCTTA at the cDNA level and p.Tyr1544Ter (Y1544X) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AATA[delCTTA]GTGA. The deletion creates a nonsense variant, which changes a Tyrosine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.4632_4635delCTTA, previously reported as ATM 4630del4, has been observed in at least three Ataxia-Telangiectasia families, one of which included an observation of this variant in the homozygous state in an individual with Ataxia-Telangiectasia (Sandoval 1999, Laake 2000). This variant is considered likely pathogenic.
Ambry Genetics	RCV000493466	SCV000581473	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	The c.4632_4635delCTTA pathogenic mutation, located in coding exon 30 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 4632 to 4635, causing a translational frameshift with a predicted alternate stop codon (p.Y1544*). This alteration has been reported in multiple individuals with a clinical diagnosis of ataxia telangiectasia (Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8(1):69-79; Laake K et al. Hum. Mutat. 2000 Sep;16(3):232-46). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697122	SCV000825716	pathogenic	Ataxia-telangiectasia syndrome	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1544*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9887333, 10980530). This variant is also known as 4630del4. ClinVar contains an entry for this variant (Variation ID: 420011). For these reasons, this variant has been classified as Pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310116	SCV001499658	pathogenic	Familial cancer of breast	2020-04-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001310116	SCV004207539	pathogenic	Familial cancer of breast	2023-10-19	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000697122	SCV004801947	pathogenic	Ataxia-telangiectasia syndrome	2023-11-03	criteria provided, single submitter	clinical testing	The following ACMG criteria is used: PVS1, PM2_Supporting (not reported in gnomAD), PM3_Supporting (detected in trans with a pathogenic variant). The variant has been described in several patients with with ataxia telangiectasia PMID: 12815592; 9887333; 10980530
Myriad Genetics, Inc.	RCV001310116	SCV004933510	pathogenic	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000481245	SCV005090393	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing