ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3154-2A>G (rs730881357)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211994 SCV000209718 pathogenic not provided 2017-03-03 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.3154-2A>G or IVS21-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 21 of the ATM gene. The variant destroys a canonical splice acceptor site and has been demonstrated to result in the use of a cryptic splice site, causing a frameshift and premature truncation of the protein product (Laake 2000). This variant, also reported as IVS23-2A>G using alternate nomenclature, has been reported in the compound heterozygous state in at least one individual with ataxia-telangiectasia (Laake 2000). Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000159707 SCV000216964 pathogenic Hereditary cancer-predisposing syndrome 2018-11-06 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Invitae RCV000206276 SCV000259237 pathogenic Ataxia-telangiectasia syndrome 2019-11-16 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 21 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been observed in trans with a pathogenic variant in an individual affected with ataxia-telangiectasia (PMID: 10980530). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. It is also known as IVS23-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 181940). Experimental studies have shown that variants affecting this splice acceptor site result in the utilization of a cryptic splice site in intron 21. This leads to the insertion of 14 nucleotides into exon 22, causing a frameshift and premature stop codon (PMID: 10980530, 24422204). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and 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 RCV000206276 SCV000678117 pathogenic Ataxia-telangiectasia syndrome 2017-05-24 criteria provided, single submitter clinical testing
Color RCV000159707 SCV000905171 pathogenic Hereditary cancer-predisposing syndrome 2018-05-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000206276 SCV001362663 pathogenic Ataxia-telangiectasia syndrome 2019-10-07 criteria provided, single submitter clinical testing Variant summary: ATM c.3154-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing as resulting in the insertion of 14 nucleotides from intron 21 into the transcript, causing a frameshift mutation that disrupts the 3'-AG splice site (p.Ala1052Phefs*17) (Jeong_2014). The variant was absent in 251096 control chromosomes. c.3154-2A>G has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Laake_2000), individuals undergoing cancer panel testing (Susswein_2016) and at-least one patient with Oesophageal cancer in whom it was grouped among genes known to be associated to a cancer predisposition but as unlikely to have explained the associated cancer phenotype (Bertelsen_2019). These data indicate that the variant may be associated with disease. Five 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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