ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3993+1G>A (rs200196781)

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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 RCV000129961 SCV000184785 pathogenic Hereditary cancer-predisposing syndrome 2020-03-23 criteria provided, single submitter clinical testing The c.3993+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 25 of the ATM gene. This alteration has been described in several ataxia-telangiectasia families (Laake K et al. Hum. Mutat. 2000; 16:232-46; Mitui M et al. Hum. Mutat. 2003; 22:43-50). This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). This alteration has also been identified in patients with pancreatic cancer (Young EL et al. BMC Cancer, 2018 Jun;18:697). 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 donor splice site; however, direct evidence is insufficient at this time (Ambry internal data). Of note, this alteration is also designated as IVS28+1G>A in published literature. 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 pathogenic.
Invitae RCV000228950 SCV000282950 pathogenic Ataxia-telangiectasia syndrome 2020-07-19 criteria provided, single submitter clinical testing This sequence change affects a donor 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 (rs200196781, ExAC 0.005%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in multiple individuals affected with ataxia-telangiectasia (PMID: 10980530, 12815592). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as IVS28+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 141447). 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). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000438634 SCV000515987 pathogenic not provided 2019-05-21 criteria provided, single submitter clinical testing Canonical splice site variant 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: 15390180, 12815592, 15039971, 29945567, 10980530, 26976419, 25186627)
Counsyl RCV000228950 SCV000678090 pathogenic Ataxia-telangiectasia syndrome 2017-06-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129961 SCV000687508 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-05 criteria provided, single submitter clinical testing

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