Submissions for variant NM_000051.4(ATM):c.8876_8879del (p.Asp2959fs)

dbSNP: rs786204726

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169561	SCV000221056	likely pathogenic	Ataxia-telangiectasia syndrome	2015-01-21	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169561	SCV000283096	pathogenic	Ataxia-telangiectasia syndrome	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp2959Glyfs*3) 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 (rs770704493, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 12815592, 27664052). This variant is also known as 8875_8878delGACT and 8874_8877delTGAC. ClinVar contains an entry for this variant (Variation ID: 189140). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000236349	SCV000293443	pathogenic	not provided	2023-06-04	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; Also known as c.8874_8877delTGAC and c.8875_8878delGACT; This variant is associated with the following publications: (PMID: 28888541, 25479140, 31206626, 29922827, 23807571, 25614872, 36414972, 33280026, 12815592, 27664052)
Ambry Genetics	RCV000494628	SCV000581454	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-14	criteria provided, single submitter	clinical testing	The c.8876_8879delACTG pathogenic mutation, located in coding exon 61 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 8876 to 8879, causing a translational frameshift with a predicted alternate stop codon (p.D2959Gfs*3). This mutation has been previously identified in three individuals with ataxia telangiectasia, two of whom carried a second truncating ATM mutation (Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Carranza D et al. Neuromolecular Med. 2017 Mar;19:161-174). Of note, this alteration is also designated as 8874_8877delTGAC and 8875_8878delGACT in published literature. 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	RCV000494628	SCV000903724	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 62 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 been identified in 3/251380 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	RCV000169561	SCV001363786	pathogenic	Ataxia-telangiectasia syndrome	2019-11-07	criteria provided, single submitter	clinical testing	Variant summary: ATM c.8876_8879delACTG (p.Asp2959GlyfsX3) 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. The variant allele was found at a frequency of 1.2e-05 in 251380 control chromosomes (gnomAD). c.8876_8879delACTG has been reported in the literature in homozygous and compound heterozygous individuals affected with Ataxia-Telangiectasia (Carranza_2017, Mitui_2003). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrate the variant to cause absence of ATM protein expression and to confer intermediate radiosensitivity (Carranza_2017). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=4) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000494628	SCV001911492	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.8876_8879del (p.Asp2959Glyfs*3) frameshift variant is predicted to result in a premature stop codon that leads to a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It has an allele frequency of 0.0013%, (3/236,852 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0058%, (2/34,246 alleles) in the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It has been described in trans with the likely pathogenic ATM variant c.8977C>T in an ataxia-telangiectasia proband and in homozygosis in another, which awards 1.5 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3; PMID: 12815592, 27664052). Lymphoblastoid cell lines of the homozygous patient showed no ATM protein expression and intermediate radiosensitivity (PS3_Supporting; PMID: 27664052). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM3 + PS3_Supporting (PMID: 33280026).
Revvity Omics, Revvity	RCV000169561	SCV002022377	pathogenic	Ataxia-telangiectasia syndrome	2020-06-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002283463	SCV002571100	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2019-11-25	criteria provided, single submitter	clinical testing	This variant has been previously reported as pathogenic [PMID 12815592]. Defects in ATM are the cause of ataxia telangiectasia (AT) [MIM:208900], an autosomal recessive disorder characterized by progressive cerebellar ataxia, dilation of the blood vessels in the conjunctiva and eyeballs, immunodeficiency, growth retardation and sexual immaturity. Patients have a strong predisposition to cancer; about 30% of patients develop tumors, particularly lymphomas and leukemias. Cells from affected individuals are highly sensitive to damage by ionizing radiation and resistant to inhibition of DNA synthesis following irradiation.
Baylor Genetics	RCV003468847	SCV004209497	pathogenic	Familial cancer of breast	2023-12-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003468847	SCV004931937	pathogenic	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Natera, Inc.	RCV000169561	SCV002085047	pathogenic	Ataxia-telangiectasia syndrome	2021-03-05	no assertion criteria provided	clinical testing