Submissions for variant NM_000051.4(ATM):c.370_374del (p.Ile124fs)

dbSNP: rs2079237399

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001036625	SCV001199998	pathogenic	Ataxia-telangiectasia syndrome	2023-06-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 835684). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 10817650). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile124Glyfs*8) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001036625	SCV002041575	pathogenic	Ataxia-telangiectasia syndrome	2021-11-07	criteria provided, single submitter	clinical testing	Variant summary: ATM c.370_374delATCAT (p.Ile124GlyfsX8) 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 251154 control chromosomes. c.370_374delATCAT has been reported in the literature in individuals affected with Ataxia-Telangiectasia (example, Li_2000). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV003238830	SCV003936570	pathogenic	not provided	2022-12-28	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Identified in a patient with ataxia-telangiectasia (Li and Swift, 2000); This variant is associated with the following publications: (PMID: 10817650)
Ambry Genetics	RCV003353115	SCV004053937	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-13	criteria provided, single submitter	clinical testing	The c.370_374delATCAT pathogenic mutation, located in coding exon 4 of the ATM gene, results from a deletion of 5 nucleotides at nucleotide positions 370 to 374, causing a translational frameshift with a predicted alternate stop codon (p.I124Gfs*8). This mutation has been identified in a cohort of patients with ataxia-telangiectasia (Li A et al. Am J Med Genet, 2000 May;92:170-7). 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.