ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5712dup (p.Ser1905fs) (rs587781730)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129923 SCV000184741 pathogenic Hereditary cancer-predisposing syndrome 2019-02-26 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000212031 SCV000209623 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing This duplication of one nucleotide in ATM is denoted c.5712dupA at the cDNA level and p.Ser1905IlefsX25 (S1905IfsX25) at the protein level. The normal sequence, with the base that is duplicated in braces, is TAAAAA[A]TCAC. The duplication causes a frameshift, which changes a Serine to an Isoleucine at codon 1905, and creates a premature stop codon at position 25 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.5712dupA has been observed in the compound heterozygous state with another ATM pathogenic variant in at least three individuals with ataxia-telangiectasia (Gilad 1996, Becker-Catania 2000, Mitui 2005). It has also been observed in at least two individuals undergoing hereditary cancer multigene testing (LaDuca 2014, Tung 2015). We consider this variant to be pathogenic.
Counsyl RCV000169006 SCV000220146 likely pathogenic Ataxia-telangiectasia syndrome 2014-03-07 criteria provided, single submitter literature only
Invitae RCV000169006 SCV000547052 pathogenic Ataxia-telangiectasia syndrome 2020-01-08 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 38 of the ATM mRNA (c.5712dupA), causing a frameshift at codon 1905. This creates a premature translational stop signal (p.Ser1905Ilefs*25) and 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: 8845835, 10873394, 16266405, 10817650) and in an individual affected with pancreatic cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 141416). 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 RCV000129923 SCV000682282 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Mendelics RCV000169006 SCV000838556 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169006 SCV000916572 pathogenic Ataxia-telangiectasia syndrome 2018-04-09 criteria provided, single submitter clinical testing Variant summary: ATM c.5712dupA (p.Ser1905IlefsX25) 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. The variant allele was found at a frequency of 8.1e-06 in 245942 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.1e-06 vs 4.00e-03), allowing no conclusion about variant significance. The variant, c.5712dupA, has been reported in the literature in individuals affected with Ataxia-Telangiectasia, breast, and pancreatic cancer (Susswein_2016, Tung_2015, Gilad_1996). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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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