Submissions for variant NM_000051.4(ATM):c.3369del (p.Tyr1124fs)

dbSNP: rs587781752

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129958	SCV000184782	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-07	criteria provided, single submitter	clinical testing	The c.3369delA pathogenic mutation located in coding exon 22 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 3369, causing a translational frameshift with a predicted alternate stop codon. This alteration was reported in the compound heterozygous state with a second pathogenic mutation in ATM in an individual diagnosed with classic ataxia telangiectasia (Bhatt N et al. Stem Cell Res. 2016 09;17(2):296-305. 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.
Color Diagnostics, LLC DBA Color Health	RCV000129958	SCV001347416	pathogenic	Hereditary cancer-predisposing syndrome	2019-09-11	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 23 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. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001849926	SCV002240387	pathogenic	Ataxia-telangiectasia syndrome	2021-01-21	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 141444). This sequence change creates a premature translational stop signal (p.Tyr1124Thrfs*2) 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).
Myriad Genetics, Inc.	RCV004019734	SCV004931153	pathogenic	Familial cancer of breast	2024-01-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.