Submissions for variant NM_000051.4(ATM):c.7705_7706del (p.Arg2568_Asp2569insTer)

dbSNP: rs759965045

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204947	SCV000261175	pathogenic	Ataxia-telangiectasia syndrome	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp2569*) 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 (rs759965045, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 10330348, 10817650, 12815592). This variant is also known as 7705delGA and 7704_7705delAG. ClinVar contains an entry for this variant (Variation ID: 220550). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000214581	SCV000275917	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-18	criteria provided, single submitter	clinical testing	The c.7705_7706delGA pathogenic mutation, located in coding exon 51 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 7705 to 7706, causing a translational frameshift with a predicted alternate stop codon (p.D2569*). This mutation has been identified in multiple families affected with ataxia-telangiectasia (A-T) (Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50). This mutation was also detected during the analysis of 49 cell lines derived from individuals with A-T (Teraoka S et al. Am J Hum Genet. 1999 Jun;64(6):1617-31). 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.
Counsyl	RCV000204947	SCV000486046	likely pathogenic	Ataxia-telangiectasia syndrome	2016-03-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000478786	SCV000565939	pathogenic	not provided	2022-08-08	criteria provided, single submitter	clinical testing	Observed in the heterozygous state in individuals with a personal or family history of cancer consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (Quezada Urban et al., 2018; Lu et al., 2019); Observed with another pathogenic variant in ATM in unrelated patients with ataxia telangiectasia in published literature; however, it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Li et al., 2000; Mitui et al., 2003); Nonsense 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); This variant is associated with the following publications: (PMID: 29025585, 10330348, 10817650, 12815592, 30128536, 30262796, 29625052, 26689913, 28888541, 29922827, 34871783, 34506673)
Color Diagnostics, LLC DBA Color Health	RCV000214581	SCV000682432	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-25	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 52 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (Color Health internal data), pancreatic cancer (PMID: 34506673; Color Health internal data), ovarian cancer (Color Health internal data), and gastric cancer (PMID: 29025585). This variant has also been reported in individuals affected with ataxia-telangiectasia (PMID: 10330348, 10817650, 12815592). This variant has been identified in 5/251176 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.
Illumina Laboratory Services, Illumina	RCV000204947	SCV000914480	likely pathogenic	Ataxia-telangiectasia syndrome	2018-11-13	criteria provided, single submitter	clinical testing	The ATM c.7705_7706delGA (p.Asp2569Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Asp2569Ter variant has been reported in three studies in which it was found in three individuals with ataxia telangiectasia (AT) (Teraoka et al. 1999; Mitui et al. 2003; Li et al. 2000). The variant was found in a compound heterozygous state in one Spanish individual in trans with a splice site variant, in a presumed compound heterozygous state with no second variant identified in a lymphoblastoid cell line derived from a patient with AT and in one of 268 AT chromosomes from a study of AT families in the US and Canada. The variant has also been reported with unspecified zygosity in one individual diagnosed with gastric cancer (Slavin et al. 2017). Control data are unavailable for the p.Asp2569Ter variant which is reported at a frequency of 0.000149 in the Latino population of the Genome Aggregation Database. Based on the evidence and potential impact of stop-gained variants, the p.Asp2569Ter variant is classified as likely pathogenic for ataxia telangiectasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000204947	SCV001478774	pathogenic	Ataxia-telangiectasia syndrome	2021-01-11	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7705_7706delGA (p.Asp2569X) 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 2e-05 in 251176 control chromosomes. c.7705_7706delGA has been reported in the literature in individuals affected with Ataxia-Telangiectasia and other types of cancers (Teraoka_1999, Mitui_2003, Li_2000, Lu_2015, etc). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003468954	SCV004210104	pathogenic	Familial cancer of breast	2024-01-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491961	SCV004239483	pathogenic	Breast and/or ovarian cancer	2023-02-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003468954	SCV004931148	pathogenic	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Fulgent Genetics, Fulgent Genetics	RCV005042447	SCV005680914	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2024-01-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000204947	SCV001462590	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003165498	SCV002758406	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research