ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.170G>A (p.Trp57Ter) (rs587779818)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211942 SCV000149054 pathogenic not provided 2018-01-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.170G>A at the cDNA level and p.Trp57Ter (W57X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with recessively-inherited Ataxia Telangiectasia (Li 2000). More recently, ATM Trp57Ter has been observed in several individuals, including at least two with breast cancer, one with colon cancer, one with sessile serrated polyposis, and four with pancreatic cancer (Tavtigian 2009, Goldgar 2011, Roberts 2012, Gala 2014, Susswein 2015, Seifert 2016, Bunnell 2017). Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000115145 SCV000186179 pathogenic Hereditary cancer-predisposing syndrome 2018-08-30 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000197540 SCV000253737 pathogenic Ataxia-telangiectasia syndrome 2019-12-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp57*) 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 observed in individuals affected with ataxia-telangiectasia, breast cancer, multiple sessile serrated adenomas, colon cancer, and pancreatic cancer (PMID: 10817650, 21787400, 24512911, 26681312, 27083775). It also segregated with pancreatic cancer in a single family (PMID: 22585167). ClinVar contains an entry for this variant (Variation ID: 127341). 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 RCV000115145 SCV000292162 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Counsyl RCV000197540 SCV000487229 pathogenic Ataxia-telangiectasia syndrome 2016-11-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000211942 SCV000805503 pathogenic not provided 2017-06-12 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000211942 SCV000927698 pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000197540 SCV001337764 pathogenic Ataxia-telangiectasia syndrome 2020-01-13 criteria provided, single submitter clinical testing Variant summary: ATM c.170G>A (p.Trp57X) 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 was absent in 250818 control chromosomes (gnomAD). c.170G>A has been reported in the literature in multiple compound heterozygous individuals, who were affected with the classic- or variant form of Ataxia-Telangiectasia (Li_2000, Nahas_2009, Schon_2019). The variant was also found in heterozygous individuals affected with various tumor phenotypes, e.g. pancreatic cancer (Roberts_2012, Shindo_2017), where the variant was reported to segregate with the disease in one family (Roberts_2012). These data indicate that the variant is likely to be associated with disease. Seven 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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