ClinVar Miner

Submissions for variant NM_001351834.2(ATM):c.3245_3247delinsTGAT (p.His1082fs) (rs587776549)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235102 SCV000209627 pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing This deletion of three nucleotides and insertion of four nucleotides in ATM is denoted c.3245_3247delATCinsTGAT at the cDNA level and p.His1082LeufsX14 (H1082LfsX14) at the protein level. The variant causes a frameshift, which changes a Histidine to a Leucine at codon 1082, and creates a premature stop codon at position 14 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.3245_3247delATCinsTGAT has been observed in at least one individual with breast cancer (Chen 1998). Additionally, this variant has been reported in the homozygous or compound heterozygous state in several individuals with Ataxia-telangiectasia and is suggested to be a Norwegian founder variant (Laake 1998, Telatar 1998, Laake 2000, Stray-Pederson 2007, Du 2008). We consider this variant to be pathogenic.
Ambry Genetics RCV000159638 SCV000216382 pathogenic Hereditary cancer-predisposing syndrome 2018-03-14 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)
Invitae RCV000003172 SCV000259626 pathogenic Ataxia-telangiectasia syndrome 2019-01-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His1082Leufs*14) 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 breast or prostate cancer (PMID: 9537233, 8797579, 27084275), and is a common cause of ataxia-telangiectasia in the Norwegian population (PMID: 9443866, 9781027, 10980530). ClinVar contains an entry for this variant (Variation ID: 3033). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000003172 SCV000485150 pathogenic Ataxia-telangiectasia syndrome 2016-03-10 criteria provided, single submitter clinical testing
Color RCV000159638 SCV000682111 pathogenic Hereditary cancer-predisposing syndrome 2016-05-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000003172 SCV000916538 pathogenic Ataxia-telangiectasia syndrome 2017-11-09 criteria provided, single submitter clinical testing Variant summary: The ATM c.3245_3247delinsTGAT (p.His1082LeufsX14) 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 is absent in 30972 control chromosomes (gnomAD). Multiple publications have cited the variant in affected A-T patients and has been indicated to be a Norwegian founder mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
OMIM RCV000003172 SCV000023330 pathogenic Ataxia-telangiectasia syndrome 2000-09-01 no assertion criteria provided literature only
GeneReviews RCV000003172 SCV000328290 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only

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