ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6404_6405insTT (p.Leu2135_Arg2136insTer) (rs587782554)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000582077 SCV000687694 pathogenic Hereditary cancer-predisposing syndrome 2015-01-20 criteria provided, single submitter clinical testing
Counsyl RCV000206421 SCV000486857 likely pathogenic Ataxia-telangiectasia syndrome 2016-08-24 criteria provided, single submitter clinical testing
GeneDx RCV000235780 SCV000292474 pathogenic not provided 2017-02-22 criteria provided, single submitter clinical testing This insertion of 2 nucleotides is denoted ATM c.6404_6405insTT at the cDNA level and p.Arg2136Ter (R2136X) at the protein level. The normal sequence, with the bases that are inserted in brackets, is CTCT[insTT]AAGA. The insertion creates a nonsense variant, which changes an Arginine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.6404_6405insTT, previously reported as 6404insTT using alternate nomenclature, has been observed in several individuals with Ataxia-telangiectasia (Telatar 1996, Stankovic 1998, Reiman 2011) as well as in affected individuals undergoing evaluation for hereditary breast or ovarian cancer (Churpek 2015, Thompson 2016). This variant is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000206421 SCV000916597 pathogenic Ataxia-telangiectasia syndrome 2018-09-24 criteria provided, single submitter clinical testing Variant summary: ATM c.6404_6405insTT (p.Arg2136X) 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 7.3e-06 in 275474 control chromosomes (gnomAD). The variant, c.6404_6405insTT, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Micol_2011, Telatar_1996) and breast cancer (Churpek_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.
Invitae RCV000206421 SCV000261563 pathogenic Ataxia-telangiectasia syndrome 2018-05-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg2136*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587782554, ExAC 0.002%). This variant has been reported in the literature in individuals with ataxia-telangiectasia (PMID: 8659541, 9463314, 21792198) and an individual with breast cancer (PMID: 25428789). This variant is also known as 6404insTT in the literature. ClinVar contains an entry for this variant (Variation ID: 220763). 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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