ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2922-1G>T (rs1555084931)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV000581238 SCV000687427 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-18 criteria provided, single submitter clinical testing This variant causes a G to T nucleotide substitution at the -1 position of intron 19 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with colorectal cancer (PMID: 31118792). 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.
Counsyl RCV000667991 SCV000792527 likely pathogenic Ataxia-telangiectasia syndrome 2017-06-29 criteria provided, single submitter clinical testing
Invitae RCV000667991 SCV001394310 likely pathogenic Ataxia-telangiectasia syndrome 2019-06-06 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 19 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). Disruption of this splice site has been observed in an individual with clinical features of ataxia-telangiectasia (PMID: 22213089). ClinVar contains an entry for this variant (Variation ID: 490499). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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