ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4437-1G>C (rs759520465)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216400 SCV000275817 pathogenic Hereditary cancer-predisposing syndrome 2020-09-18 criteria provided, single submitter clinical testing The c.4437-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 29 of the ATM gene. This alteration has been reported in a homozygous state in a Hispanic-American individual with classic ataxia-telangiectasia (Mitui M et al. Hum. Mutat. 2003 Jul; 22(1):43-50). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, 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 disease-causing mutation.
GeneDx RCV000486776 SCV000568323 pathogenic not provided 2021-06-15 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 significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 12815592)
Invitae RCV000530451 SCV000622501 likely pathogenic Ataxia-telangiectasia syndrome 2020-10-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 29 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 (rs759520465, ExAC 0.01%). This variant has been reported as homozygous in an individual affected with autosomal recessive ataxia-telangiectasia (PMID: 12815592). This variant is also known as IVS31-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 231843). 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.
Counsyl RCV000530451 SCV000798327 likely pathogenic Ataxia-telangiectasia syndrome 2018-03-09 criteria provided, single submitter clinical testing
Color Health, Inc RCV000216400 SCV001340523 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-25 criteria provided, single submitter clinical testing

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