Submissions for variant NM_000051.4(ATM):c.4019_4029del (p.Leu1340fs)

dbSNP: rs1057517140

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410743	SCV000486809	likely pathogenic	Ataxia-telangiectasia syndrome	2016-08-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410743	SCV000547017	pathogenic	Ataxia-telangiectasia syndrome	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1340Cysfs*10) 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 (no rsID available, gnomAD 0.008%). 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: 371269). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000564318	SCV000667837	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-15	criteria provided, single submitter	clinical testing	The c.4019_4029del11 pathogenic mutation, located in coding exon 26 of the ATM gene, results from a deletion of 11 nucleotides at nucleotide positions 4019 to 4029, causing a translational frameshift with a predicted alternate stop codon (p.L1340Cfs*10). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Baylor Genetics	RCV003470348	SCV004212148	likely pathogenic	Familial cancer of breast	2022-12-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000564318	SCV004360923	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-19	criteria provided, single submitter	clinical testing	This variant deletes 11 nucleotides in exon 27 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 has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/279966 chromosomes 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.
Myriad Genetics, Inc.	RCV003470348	SCV004933815	pathogenic	Familial cancer of breast	2024-01-23	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
GeneDx	RCV004725199	SCV005331724	pathogenic	not provided	2024-01-22	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 significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23807571, 25614872)
PreventionGenetics, part of Exact Sciences	RCV004739711	SCV005347928	pathogenic	ATM-related disorder	2024-03-28	no assertion criteria provided	clinical testing	The ATM c.4019_4029del11 variant is predicted to result in a frameshift and premature protein termination (p.Leu1340Cysfs*10). It has been reported in compound heterozygous state with c.2817del (p.Lys940Asnfs*9) in a patient with ataxia-telangiectasia (Table 3, Quinn et al. 2020. PubMed ID: 32462469). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/). Frameshift variants in ATM are expected to be pathogenic. In ClinVar, this variant has interpretations of likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/371269/). This variant is interpreted as pathogenic.