ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3994-2A>G (rs587782276)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131133 SCV000186065 pathogenic Hereditary cancer-predisposing syndrome 2019-04-18 criteria provided, single submitter clinical testing The c.3994-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 26 in the ATM gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native acceptor splice site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a pathogenic mutation.
Invitae RCV000198837 SCV000253669 likely pathogenic Ataxia-telangiectasia syndrome 2020-04-09 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 26 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs587782276, ExAC 0.006%). This variant has been reported in an individual with a personal history of breast cancer and family history of pancreatic cancer (PMID: 28956312) and in an individual undergoing hereditary cancer multi-gene panel testing for which clinical information was not provided (PMID: 24763289). ClinVar contains an entry for this variant (Variation ID: 142167). 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: 25614872, 23807571). 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.
Color Health, Inc RCV000131133 SCV000904688 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-21 criteria provided, single submitter clinical testing
GeneDx RCV001580458 SCV001817496 likely pathogenic not provided 2021-03-11 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29922827, 23807571, 25614872, 28956312, 28152038, 24763289)

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