ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6914_6915AG[1] (p.Leu2307fs) (rs878853535)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234351 SCV000283029 pathogenic Ataxia-telangiectasia syndrome 2019-05-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu2307Cysfs*65) 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 the literature in an individual affected with ataxia-telangiectasia (PMID: 9463314). ClinVar contains an entry for this variant (Variation ID: 236760). 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 RCV000235684 SCV000293439 pathogenic not provided 2018-11-21 criteria provided, single submitter clinical testing This deletion of two nucleotides in ATM is denoted c.6916_6917delAG at the cDNA level and p.Leu2307CysfsX65 (L2307CfsX65) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GCAG[delAG]TCTT. The deletion causes a frameshift, which changes a Leucine to a Cysteine at codon 2307, and creates a premature stop codon at position 65 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.6916_6917delAG has been observed in at least one individual with ataxia-telangiectasia (Stankovic 1998, Carney 2012) and in several individuals with breast cancer (Decker 2017, Hauke 2018). We consider this variant to be pathogenic.
Ambry Genetics RCV001025799 SCV001188057 pathogenic Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV001025799 SCV001358585 pathogenic Hereditary cancer-predisposing syndrome 2019-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000234351 SCV001431915 pathogenic Ataxia-telangiectasia syndrome 2020-08-23 criteria provided, single submitter clinical testing Variant summary: ATM c.6916_6917delAG (p.Leu2307CysfsX65) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251316 control chromosomes. c.6916_6917delAG has been reported in the literature in individuals affected with Ataxia-Telangiectasia (e.g. Stankovic_1998, Thompson_2005, Carney_2012, Jackson_2016). These data indicate that the variant may be associated with disease. The variant has also been reported in individuals affected with breast cancer (e.g. Jackson_2016) and ovarian cancer (e.g. Arvai_2019). 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. Based on the evidence outlined above, the variant was classified as pathogenic.

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