ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4776+1G>T (rs771117943)

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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 RCV000573615 SCV000660445 pathogenic Hereditary cancer-predisposing syndrome 2020-02-10 criteria provided, single submitter clinical testing The c.4776+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 30 of the ATM gene. This nucleotide position is highly conserved in available vertebrate species. This mutation has been seen in conjunction with another pathogenic ATM mutation in a 9 year old female with severe ataxia-telangiectasia (A-T) (Broccoletti T et al. Eur. J. Neurol. 2011 Apr;18:564-70). In another study, this alteration was identified with a missense ATM alteration in an individual with atypical A-T and was reported to cause skipping of coding exon 30 (Fiévet A et al. Hum. Mutat., 2019 10;40:1713-1730). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish this splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Health, Inc RCV000573615 SCV000687567 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-18 criteria provided, single submitter clinical testing
Counsyl RCV000669160 SCV000793880 likely pathogenic Ataxia-telangiectasia syndrome 2017-09-12 criteria provided, single submitter clinical testing
Invitae RCV000669160 SCV000823408 likely pathogenic Ataxia-telangiectasia syndrome 2018-03-25 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 31 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 (rs771117943, ExAC 0.02%). This variant has been reported in an individual affected with ataxia-telangiectasia (PMID: 20840352). ClinVar contains an entry for this variant (Variation ID: 478920). 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.
GeneDx RCV001560132 SCV001782480 likely pathogenic not provided 2020-07-06 criteria provided, single submitter clinical testing Canonical splice site variant demonstrated to result in an in-frame deletion of exon 31 (Fivet 2019); Observed in an individual with familial breast cancer; however, the variant was not found in an affected sister (Bubien 2017); Observed with other ATM variants in unrelated patients with ataxia-telangiectasia, but it was not reported whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Broccoletti 2011, Fivet 2019); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31050087, 22763152, 28691344, 20840352)

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