Submissions for variant NM_000051.4(ATM):c.1355del (p.Thr452fs)

dbSNP: rs587781776

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV003467128	SCV004565380	pathogenic	Familial cancer of breast	2024-01-25	reviewed by expert panel	curation	The c.1355del (p.Thr452AsnfsTer21) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent from gnomAD v2.1.1. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 9463314, 10234507, 26896183). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_Supporting, PM2_Supporting).
Ambry Genetics	RCV000130017	SCV000184842	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	The c.1355delC pathogenic mutation, located in coding exon 9 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 1355, causing a translational frameshift with a predicted alternate stop codon (p.T452Nfs*21). This mutation has been reported in multiple individuals with ataxia-telangiectasia (Stankovic T et al. Am. J. Hum. Genet. 1998; 62:334-45, Izatt L et al. Eur. J. Hum. Genet. 1999; 7:310-20). 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466554	SCV000546966	pathogenic	Ataxia-telangiectasia syndrome	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr452Asnfs*21) 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 (A-T) (PMID: 9463314, 10234507, 28779002). ClinVar contains an entry for this variant (Variation ID: 141474). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000520020	SCV000616644	pathogenic	not provided	2023-09-12	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9463314, 11821961, 28152038, 28779002, 31948886, 26896183, 35154108, 32694154, 35365198, 34887416, 10234507)
Color Diagnostics, LLC DBA Color Health	RCV000130017	SCV000687303	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 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 been reported in individuals affected with ataxia-telangiectasia (PMID: 9463314, 10234507, 15928302). In at least one of these individual, this variant was reported in the compound heterozygous state (PMID 10234507). Patient-derived lymphoblastoid cell lines show reduced ATM expression (PMID: 10234507). 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.
Illumina Laboratory Services, Illumina	RCV000466554	SCV000915497	likely pathogenic	Ataxia-telangiectasia syndrome	2018-08-16	criteria provided, single submitter	clinical testing	The ATM c.1355delC (p.Thr452AsnfsTer21) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Thr452AsnfsTer21 variant has been reported in two studies in which it was found in two patients with ataxia-telangiectasia, in one in a compound heterozygous state with a second missense variant, and in the second patient in a presumed compound heterozygous state where a second variant was not specified (Stankovic et al. 1998; Izatt et al. 1999). Lymphoblastoid cell lines from both patients showed very low or no detectable protein compared with controls. Control data are unavailable for this variant. The p.Thr452AsnfsTer21 variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database. Based on the evidence, the p.Thr452AsnfsTer21 variant is classified as likely pathogenic for ataxia-telangiectasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV003467128	SCV004209491	pathogenic	Familial cancer of breast	2023-09-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467128	SCV004930361	pathogenic	Familial cancer of breast	2024-01-16	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.