ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206421 SCV000261563 pathogenic Ataxia-telangiectasia syndrome 2020-10-27 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.
GeneDx RCV000235780 SCV000292474 pathogenic not provided 2021-06-17 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 a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 27693457, 29753700, 8659541, 25428789, 26786923, 21792198, 9463314, 28779002, 27535533, 25614872, 26582918, 23807571, 21665257, 33436325)
Counsyl RCV000206421 SCV000486857 likely pathogenic Ataxia-telangiectasia syndrome 2016-08-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000582077 SCV000687694 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Ambry Genetics RCV000582077 SCV001187382 pathogenic Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing The c.6404_6405insTT pathogenic mutation (also known as p.R2136*), located in coding exon 43 of the ATM gene, results from an insertion of two nucleotides at position 6404. This changes the amino acid from an arginine to a stop codon within coding exon 43. This pathogenic mutation has been reported in one individual with ataxia-telangiectasia (Telatar M et al. Am. J. Hum. Genet. 1996 Jul;59:40-4). This alteration has also been detected in multiple individuals diagnose with breast cancer (Churpek JE et al. Breast Cancer Res. Treat. 2015 Jan;149:31-9; Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000235780 SCV001446712 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing

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