ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4373del (p.Gly1458fs) (rs587781653)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129787 SCV000184596 pathogenic Hereditary cancer-predisposing syndrome 2017-03-01 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 RCV000129787 SCV000905173 pathogenic Hereditary cancer-predisposing syndrome 2018-03-09 criteria provided, single submitter clinical testing
GeneDx RCV000254632 SCV000209619 pathogenic not provided 2016-07-11 criteria provided, single submitter clinical testing This deletion of one nucleotide in ATM is denoted c.4373delG at the cDNA level and p.Gly1458GlufsX15 (G1458EfsX15) at the protein level. The normal sequence, with the bases that are deleted in braces, is TTAG[G]AGGA. The deletion causes a frameshift, which changes a Glycine to a Glutamic Acid at codon 1458, and creates a premature stop codon at position 15 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.4373delG has been observed in multiple patients with Ataxia-Telangiectasia and has been associated with absent ATM protein expression and no residual ATM protein activity in an affected compound heterozygote (Teraoka 1999, Li 2000, Carney 2012). We consider this variant to be pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000709710 SCV000839885 pathogenic Familial cancer of breast 2017-10-30 criteria provided, single submitter clinical testing The c.4373delG frame shift variant is predicted to yield loss of function transcripts/proteins of ATM gene, which is one of mechanisms causing Ataxia-telangiectasia. This variant is extremely rare in general population (1 in 246014 by gnomad) and observed in multiple ataxia-telangiectasia patients (PMID:10330348, 22649200). It has been also observed in other clinical labs and reported as a pathogenic. Based on the above evidences, we interpret this variant as pathogenic.
Invitae RCV000474596 SCV000546761 pathogenic Ataxia-telangiectasia syndrome 2018-09-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly1458Glufs*15) 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, 22649200) and in an individual affected with prostate cancer (PMID: 27433846). 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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