Submissions for variant NM_000051.4(ATM):c.8814_8824del (p.Met2938fs)

gnomAD frequency: 0.00001  dbSNP: rs758814126

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000408957	SCV000486255	likely pathogenic	Ataxia-telangiectasia syndrome	2016-04-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000483094	SCV000568342	pathogenic	not provided	2019-06-24	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; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 9450906, 9497252, 9887333, 23454770, 10864201, 17910737, 29625052)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000408957	SCV000622856	pathogenic	Ataxia-telangiectasia syndrome	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met2938Ilefs*14) 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 present in population databases (rs758814126, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9497252, 9887333, 17910737, 23454770). This variant is also known as 8814del11. ClinVar contains an entry for this variant (Variation ID: 370841). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000571341	SCV000668079	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-14	criteria provided, single submitter	clinical testing	The c.8814_8824del11 pathogenic mutation, located in coding exon 60 of the ATM gene, results from a deletion of 11 nucleotides at positions 8814 to 8824, causing a translational frameshift with a predicted alternate stop codon (p.M2938Ifs*14). This alteration has been detected in the compound heterozygous state in individuals diagnosed with ataxia telangiectasia (AT) (Gilad S et al. Am. J. Hum. Genet. 1998 Mar;62:551-61; Cavalieri S et al. Ann. Hum. Genet. 2008 Jan;72:10-8). 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	RCV000571341	SCV000682520	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-19	criteria provided, single submitter	clinical testing	This variant deletes 11 nucleotides in exon 61 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 (also known as 8814del11 in the literature) has been reported in individuals affected with ataxia-telangiectasia (PMID: 9887333, 10864201, 17910737, 23454770). This variant has also been identified in 2/251404 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000408957	SCV001426788	pathogenic	Ataxia-telangiectasia syndrome	2020-07-12	criteria provided, single submitter	clinical testing	Variant summary: ATM c.8814_8824del11 (p.Met2938IlefsX14) 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 allele was found at a frequency of 8e-06 in 251404 control chromosomes. c.8814_8824del11 has been reported in the literature in individuals affected with Ataxia-Telangiectasia (e.g. Gilad_1998, Sandoval_1999, Cavalieri_2008). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating ATM protein function in patient cells with this mutation in compound heterozygosity with a second pathogenic mutation. These studies report reduced ATM protein levels and reduced ATM-dependent activities in patient-derived cell lines, however the contributions of the individual variants to the observed phenotypes were not studied (e.g. Gilad_1998, Delia_2000, Prodosmo_2013). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003470335	SCV004212077	pathogenic	Familial cancer of breast	2023-03-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003470335	SCV004932535	pathogenic	Familial cancer of breast	2024-02-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.