ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.5326G>T (p.Glu1776Ter)

dbSNP: rs1555106321
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564720 SCV000668126 pathogenic Hereditary cancer-predisposing syndrome 2021-09-30 criteria provided, single submitter clinical testing The p.E1776* pathogenic mutation (also known as c.5326G>T), located in coding exon 35 of the ATM gene, results from a G to T substitution at nucleotide position 5326. This changes the amino acid from a glutamic acid to a stop codon within coding exon 35. This alteration has been reported in conjunction with a second ATM alteration, IVS53-2A>C, in an individual affected with ataxia telangiectasia (Laake K et al. Hum Mutat, 2000 Sep;16:232-46). This variant was reported in 2/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
GeneDx RCV000657611 SCV000779353 pathogenic not provided 2022-03-17 criteria provided, single submitter clinical testing 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: 25525159, 10980530)
Labcorp Genetics (formerly Invitae), Labcorp RCV001218574 SCV001390462 pathogenic Ataxia-telangiectasia syndrome 2024-01-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1776*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 10980530). ClinVar contains an entry for this variant (Variation ID: 482731). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001218574 SCV002500147 likely pathogenic Ataxia-telangiectasia syndrome 2022-03-07 criteria provided, single submitter clinical testing Variant summary: ATM c.5326G>T (p.Glu1776X) 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 was absent in 250556 control chromosomes (gnomAD). c.5326G>T has been reported in the literature in a compound heterozygous individuals affected with Ataxia-Telangiectasia (Laake_2000). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 2/60466 cases, but was also found in 2/53461 controls (Dorling_2021 through LOVD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Sema4, Sema4 RCV000564720 SCV002528409 pathogenic Hereditary cancer-predisposing syndrome 2022-03-09 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000657611 SCV002760584 pathogenic not provided 2023-08-15 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002497210 SCV002808713 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2022-03-08 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV004024502 SCV004930531 pathogenic Familial cancer of breast 2024-01-25 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.

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