Submissions for variant NM_000051.4(ATM):c.2521del (p.Asp841fs)

dbSNP: rs1175457710

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000552064	SCV000622336	pathogenic	Ataxia-telangiectasia syndrome	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp841Ilefs*6) 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: 9792409). This variant is also known as 2519delG. ClinVar contains an entry for this variant (Variation ID: 453419). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000777225	SCV000912916	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 17 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV000777225	SCV001176685	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-26	criteria provided, single submitter	clinical testing	The c.2521delG variant, located in coding exon 16 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 2521, causing a translational frameshift with a predicted alternate stop codon (p.D841Ifs*6). This alteration, referred to as c.2519delG, was identified in conjunction with a second ATM alteration in an individual with features of ataxia telangiectasia (Broeks A et al. Hum. Mutat., 1998;12:330-7). This variant has also been identified in at least one patient with a personal and family history of breast and/or ovarian cancer (Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-817). 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.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000552064	SCV001338762	pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing	In the ATM gene (transcript: NM_000051) the heterozygous frame shift variant c.2521del; p.Asp841Ilefs*6 in exon 17 was detected. This variant was inherited from the mother. The germline variant leads to a shift in the reading frame and, after five incorrect amino acids, to a premature stop codon. This variant is not recorded in population-related databases. In the phenotype-related database LOVD it is listed once as pathogenic and once as a variant of unclear functional relevance, in HGMD it is classified as pathogenic and once as likely pathogenic and in ClinVar it is listed twice as pathogenic. The ACMG classification for this variant is: pathogenic (Class 5: PVS1, PM2, PM3, PP5).
Myriad Genetics, Inc.	RCV004023634	SCV004933363	pathogenic	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Natera, Inc.	RCV000552064	SCV001462076	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001729622	SCV001977667	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001729622	SCV001979976	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001729622	SCV002034327	pathogenic	not provided		no assertion criteria provided	clinical testing