ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1027_1030delGAAA (rs587780612)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122816 SCV000166073 pathogenic Ataxia-telangiectasia syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu343Ilefs*2) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587780612, ExAC 0.005%). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 10330348, 10817650, 12552559, 22213089, 21792198) and idiopathic perifoveal telangiectasia (PMID: 18502988). It is also known as 1024delAAAG, 1027_1030delAAAG, and 1027del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 141397). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000129901 SCV000184719 pathogenic Hereditary cancer-predisposing syndrome 2018-02-09 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),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s)
Counsyl RCV000122816 SCV000220152 likely pathogenic Ataxia-telangiectasia syndrome 2014-03-10 criteria provided, single submitter literature only
Vantari Genetics RCV000129901 SCV000266988 pathogenic Hereditary cancer-predisposing syndrome 2015-10-26 criteria provided, single submitter clinical testing
GeneDx RCV000236560 SCV000293429 pathogenic not provided 2018-03-23 criteria provided, single submitter clinical testing This deletion of 4 nucleotides in ATM is denoted c.1027_1030delGAAA at the cDNA level and p.Glu343IlefsX2 (E343IfsX2) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAAA[delGAAA]ATTT. The deletion causes a frameshift, which changes a Glutamic Acid to an Isoleucine at codon 343, and creates a premature stop codon at position 2 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.1027_1030delGAAA , also published as ATM c.1024delAAAG by alternate nomenclature, has been observed in individuals with ataxia telangiectasia who harbor a second ATM variant, and corresponding functional studies have found absent or reduced levels of ATM protein expression (Teraoka 1999, Becker-Catania 2000, Verhagen 2007, Reiman 2011, Verhagen 2012). This variant has also been reported in an individual with a personal and family history of breast cancer (Desmond 2015), and in at least two individuals with idiopathic perifoveal telangiectasia (Barbazetto 2008). We consider this variant to be pathogenic.
Color RCV000129901 SCV000681947 pathogenic Hereditary cancer-predisposing syndrome 2015-10-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000122816 SCV000694167 pathogenic Ataxia-telangiectasia syndrome 2016-05-09 criteria provided, single submitter clinical testing Variant summary: The ATM c.1027_1030delGAAA (p.Glu343Ilefs) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Trp393X, p.Gln1017X, p.Arg1466X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121026 control chromosomes but has been reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Athena Diagnostics Inc RCV000236560 SCV000840912 pathogenic not provided 2018-03-31 criteria provided, single submitter clinical testing

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