Submissions for variant NM_000051.4(ATM):c.2922-50_2940del

dbSNP: rs1555084832

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458119	SCV000546985	pathogenic	Ataxia-telangiectasia syndrome	2024-01-06	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 20 (c.2922-50_2940del) of the ATM gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 407642). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts a region of the ATM protein in which other variant(s) (p.Cys977Tyr) have been determined to be pathogenic (PMID: 34445196; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001176507	SCV001340507	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-10-14	criteria provided, single submitter	clinical testing	This variant causes a 69-nucleotide deletion encompassing the last 50 nucleotides of intron 19 and the first 19 nucleotides of exon 20 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on 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 Likely Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001543569	SCV001762231	likely pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001176507	SCV002748419	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	The c.2922-50_2940del69 intronic pathogenic mutation results from a deletion of 69 nucleotides beginning 50 nucleotides upstream from coding exon 19 and spanning 19 nucleotides into coding exon 19 of the ATM gene. This pathogenic mutation has been reported in conjunction with another pathogenic mutation in the ATM gene in a 9 year old child with ataxia telangiectasia. The c.2922-50_2940del69 mutation leads to the loss of the native splice acceptor site and the activation of a cryptic exonic splice site causing exon skipping (Bartsch O et al. Eur J Med Genet. 2012 Jan;55(1):49-55, Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Athena Diagnostics	RCV001543569	SCV002771708	likely pathogenic	not provided	2022-05-10	criteria provided, single submitter	clinical testing	This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
GeneDx	RCV001543569	SCV004169102	likely pathogenic	not provided	2023-10-16	criteria provided, single submitter	clinical testing	Intronic variant demonstrated activate a cryptic splice acceptor site, leading to the loss of the first 71 nucleotides of exon 20, also denoted exon 22 by alternate numbering, predicted to result in a frameshift and truncated protein (Bartsch et al., 2012); Observed in trans with an ATM frameshift variant in a child with atypical ataxia-telangiectasia (Bartsch et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21893220)
Baylor Genetics	RCV003463885	SCV004207031	likely pathogenic	Familial cancer of breast	2023-10-09	criteria provided, single submitter	clinical testing