ClinVar Miner

Submissions for variant NM_001351834.2(ATM):c.3802del (p.Glu1267_Val1268insTer) (rs587779834)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212002 SCV000149088 pathogenic not provided 2018-11-06 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.3802delG at the cDNA level and p.Val1268Ter (V1268X) at the protein level. The normal sequence, with the base that is deleted in brackets, is TGAG[delG]TGAA. The deletion creates a nonsense variant, changing a Valine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously reported as ATM c.3801delG using alternate nomenclature, has been observed in patients with breast and/or pancreatic cancer in the heterozygous state and has also been observed in multiple patients with ataxia telangiectasia in both the compound heterozygous and homozygous state (McConville 1996, Dork 2001, Delia 2000, Campbell 2003, Brunet 2008, Tavtigian 2009, Goldgar 2011, Roberts 2012). We consider ATM c.3802delG to be pathogenic.
Ambry Genetics RCV000115179 SCV000184776 pathogenic Hereditary cancer-predisposing syndrome 2018-03-16 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)
Invitae RCV000198788 SCV000253740 pathogenic Ataxia-telangiectasia syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val1268*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs765158119, ExAC 0.009%). This variant has been reported in individuals with ataxia-telangiectasia (A-T) as homozygous (PMID: 9887333, 10864201) or compound heterozygous with other pathogenic ATM variants (PMID: 9887333, 8755918, 25614872, 10330348, 25077176, 12815592, 23585524). It has been described as an A-T founder mutation in families from the British Isles (PMID: 9463314). In addition, it has been reported in individuals with breast cancer (PMID: 11606401, 18384426, 21787400, 16832357) and pancreatic cancer (PMID: 22585167). This variant is also known as c.3801delG in the literature. ClinVar contains an entry for this variant (Variation ID: 127374). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000198788 SCV000485724 pathogenic Ataxia-telangiectasia syndrome 2016-03-18 criteria provided, single submitter clinical testing
Color RCV000115179 SCV000682163 pathogenic Hereditary cancer-predisposing syndrome 2015-07-13 criteria provided, single submitter clinical testing
Mendelics RCV000198788 SCV000838526 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000212002 SCV000840935 pathogenic not provided 2016-01-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000198788 SCV000916584 pathogenic Ataxia-telangiectasia syndrome 2018-07-03 criteria provided, single submitter clinical testing Variant summary: ATM c.3802delG (p.Val1268X) 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 (e.g., p.Arg1466X and p.Ser1905fsX25). The variant allele was found at a frequency of 4e-05 in 276948 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.3802delG has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia as both a homozygous and compound heterozygous allele, indicating the variant is very likely to be associated with disease. At least one publication reports functional data indicating the variant significantly impairs protein expression and kinase activity in patient cells (Carranza_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785195 SCV000923763 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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