ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6095+1G>A (rs587781584)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129624 SCV000184417 likely pathogenic Hereditary cancer-predisposing syndrome 2016-06-28 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
Integrated Genetics/Laboratory Corporation of America RCV000780909 SCV000918550 likely pathogenic Ataxia-telangiectasia syndrome 2018-07-09 criteria provided, single submitter clinical testing Variant summary: ATM c.6095+1G>A 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 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 121252 control chromosomes. c.6095+1G>A has been reported in the literature in individuals affected with breast cancer from a meta-analysis of cases and controls (Tavtigian_2009). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000780909 SCV000944673 likely pathogenic Ataxia-telangiectasia syndrome 2018-09-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 41 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 observed in individuals affected with breast cancer (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 141218). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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