ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3372C>G (p.Tyr1124Ter) (rs587779833)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211999 SCV000149085 pathogenic not provided 2021-05-14 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; Observed with a pathogenic variant on the opposite allele (in trans) and in apparent homozygous state in individuals with ataxia-telangiectasia in published literature (Li 2000, Minto 2019); Observed in individuals with a personal or family history including medulloblastoma and prostate cancer (Waszak 2018, Matejcic 2020); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 10330348, 10817650, 32832836, 25525159, 26681312, 24113346, 28152038, 29753700, 30639167)
Ambry Genetics RCV000115176 SCV000186133 pathogenic Hereditary cancer-predisposing syndrome 2018-04-24 criteria provided, single submitter clinical testing The p.Y1124* pathogenic mutation (also known as c.3372C>G), located in coding exon 22 of the ATM gene, results from a C to G substitution at nucleotide position 3372. This changes the amino acid from a tyrosine to a stop codon within coding exon 22. This mutation has been reported as both heterozygous and homozygous in ataxia-telangiectasia (A-T) patients to date (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7). This alteration has also been identified in an individual with breast cancer and pulmonary carcinoid (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). 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 RCV000169463 SCV000220895 likely pathogenic Ataxia-telangiectasia syndrome 2014-11-19 criteria provided, single submitter literature only
Invitae RCV000169463 SCV000282930 pathogenic Ataxia-telangiectasia syndrome 2020-10-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr1124*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 10330348, 10817650), and an individual with breast and lung cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 127371). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000515217 SCV000611164 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115176 SCV000911665 pathogenic Hereditary cancer-predisposing syndrome 2020-08-20 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 23 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 the homozygous and heterozygous state in individuals affected with ataxia telangiectasia (PMID: 10330348, 10817650). This variant has also been reported in an individual affected with breast and lung cancer (PMID: 26681312). This variant has been identified in 1/250920 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169463 SCV000916541 pathogenic Ataxia-telangiectasia syndrome 2017-10-31 criteria provided, single submitter clinical testing Variant summary: The ATM c.3372C>G (p.Tyr1124X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 1/245674 control chromosomes (gnomAD) at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). Multiple publications have cited the variant in affected individuals diagnosed with breast cancer or Ataxia-Telangiectasia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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