ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2839-3_2839delinsGATACTA (rs786202148)

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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 RCV000164817 SCV000215500 likely pathogenic Hereditary cancer-predisposing syndrome 2017-03-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
GeneDx RCV000255634 SCV000322093 likely pathogenic not provided 2019-11-07 criteria provided, single submitter clinical testing Variant disrupting a canonical splice site in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Observed in an individual with Ataxia-telangiectasia (Mitui 2003); Also known as IVS20-3del3ins7; This variant is associated with the following publications: (PMID: 12815592, 28152038)
Invitae RCV000469912 SCV000546815 pathogenic Ataxia-telangiectasia syndrome 2018-09-24 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 18 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ataxia-telangiectasia (PMID: 12815592). This variant is also known as IVS20-3del3ins7 in the literature. ClinVar contains an entry for this variant (Variation ID: 185405). 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.
Ambry Genetics RCV000164817 SCV000672712 likely pathogenic Hereditary cancer-predisposing syndrome 2017-05-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Color Health, Inc RCV000164817 SCV000682082 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-06 criteria provided, single submitter clinical testing This variant impacts the canonical acceptor site at intron 18 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Splicing has been reported as aberrant for this variant (PMID: 12815592). This variant has been reported in an individual affected with Ataxia-Telangiectasia (PMID: 12815592). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000469912 SCV000918551 likely pathogenic Ataxia-telangiectasia syndrome 2018-07-09 criteria provided, single submitter clinical testing Variant summary: ATM c.2839-3_2839delinsGATACTA 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: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246128 control chromosomes (gnomAD). The variant, c.2839-3_2839delinsGATACTA, has been reported in the literature in at-least one individual affected with Ataxia-Telangiectasia (LaDuca_2017, Mitui_2003). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000469912 SCV001573161 pathogenic Ataxia-telangiectasia syndrome 2021-04-07 criteria provided, single submitter clinical testing

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