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
Ambry Genetics RCV000115176 SCV000186133 pathogenic Hereditary cancer-predisposing syndrome 2018-04-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000115176 SCV000911665 pathogenic Hereditary cancer-predisposing syndrome 2017-12-24 criteria provided, single submitter clinical testing
Counsyl RCV000169463 SCV000220895 likely pathogenic Ataxia-telangiectasia syndrome 2014-11-19 criteria provided, single submitter literature only
Fulgent Genetics RCV000515217 SCV000611164 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000211999 SCV000149085 pathogenic not provided 2017-09-13 criteria provided, single submitter clinical testing This variant is denoted ATM c.3372C>G at the cDNA level and p.Tyr1124Ter (Y1124X) at the protein level. The substitution creates a nonsense variant, changing a Tyrosine to a premature stop codon (TAC>TAG). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM Tyr1124Ter has been observed in the homozygous state in at least one individual with Ataxia-Telangiectasia (Li 2000). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000169463 SCV000282930 pathogenic Ataxia-telangiectasia syndrome 2018-04-15 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.

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