ClinVar Miner

Submissions for variant NM_001351834.2(ATM):c.5290del (p.Leu1764fs) (rs587779846)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235105 SCV000149119 pathogenic not provided 2018-09-21 criteria provided, single submitter clinical testing This deletion of one nucleotide in ATM is denoted c.5290delC at the cDNA level and p.Leu1764TyrfsX12 (L1764YfsX12) at the protein level. The normal sequence, with the base that is deleted in brackets, is CTAT[delC]TACA. The deletion causes a frameshift, which changes a Leucine to a Tyrosine at codon 1764 and creates a premature stop codon at position 12 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.5290delC has been reported in individuals with ataxia telangiectasia, as well in individuals with breast or lung cancer (Castellvi-Bel 1999, Teraoka 1999, Sun 2002, Renwick 2006, Lu 2015, Maxwell 2016, Decker 2017, Parry 2017). We consider this variant to be pathogenic.
Ambry Genetics RCV000115210 SCV000183971 pathogenic Hereditary cancer-predisposing syndrome 2012-12-17 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Counsyl RCV000169483 SCV000220935 likely pathogenic Ataxia-telangiectasia syndrome 2014-12-04 criteria provided, single submitter literature only
Invitae RCV000169483 SCV000253739 pathogenic Ataxia-telangiectasia syndrome 2019-12-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1764Tyrfs*12) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587779846, ExAC 0.002%). This variant has been reported in several individuals affected with ataxia-telangiectasia and breast cancer (PMID: 10330348, 10425038, 12552559, 16832357, 26681312, 22649200). ClinVar contains an entry for this variant (Variation ID: 127405). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Color RCV000115210 SCV000682261 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169483 SCV000916586 pathogenic Ataxia-telangiectasia syndrome 2018-08-03 criteria provided, single submitter clinical testing Variant summary: ATM c.5290delC (p.Leu1764TyrfsX12) 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 (eg. c.5712dupA/p.Ser1905fsX25, c.5908C>T/p.Gln1970X). The variant allele was found at a frequency of 8.3e-06 in 121178 control chromosomes. c.5290delC has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Castellvi-Bev_1999, Sun_2002, Thompson_2005). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Three 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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