Submissions for variant NM_000051.4(ATM):c.4358_4359del (p.Ile1453fs)

dbSNP: rs1555097650

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665982	SCV000790206	likely pathogenic	Ataxia-telangiectasia syndrome	2017-03-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665982	SCV001393321	pathogenic	Ataxia-telangiectasia syndrome	2022-05-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 551030). This variant is also known as c.4355_4356delAT. This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (A-T) (PMID: 15880721). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile1453Lysfs*37) 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).
Ambry Genetics	RCV002331303	SCV002632225	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-26	criteria provided, single submitter	clinical testing	The c.4358_4359delTA pathogenic mutation, located in coding exon 28 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 4358 to 4359, causing a translational frameshift with a predicted alternate stop codon (p.I1453Kfs*37). This alteration was identified in an individual diagnosed with ataxia telangiectasia (Birrell GW et al. Hum Mutat, 2005 Jun;25:593). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as c.4355_4356delAT in published literature. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000665982	SCV003844813	likely pathogenic	Ataxia-telangiectasia syndrome	2023-02-03	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4358_4359delTA (p.Ile1453LysfsX37) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251162 control chromosomes. c.4358_4359delTA has been reported in the literature in an individual affected with Ataxia-Telangiectasia (Birrell_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003465445	SCV004209472	pathogenic	Familial cancer of breast	2023-09-11	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003465445	SCV004933734	pathogenic	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.