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 2018-07-25 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000228950 SCV000282950 pathogenic Ataxia-telangiectasia syndrome 2019-12-30 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 2017-12-12 criteria provided, single submitter clinical testing This variant is denoted ATM c.3993+1G>A or IVS26+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 26 of the ATM gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant, also defined as IVS28+1G>A by alternate nomenclature, has been reported in association with ataxia telangiectasia (Laake 2000, Mitui 2003, Coutinho 2004, Cavaciuti 2005) and was co-observed with a CHEK2 pathogenic variant in a patient with bilateral breast cancer (Tung 2016). We consider this variant to be pathogenic.
Counsyl RCV000228950 SCV000678090 pathogenic Ataxia-telangiectasia syndrome 2017-06-14 criteria provided, single submitter clinical testing
Color RCV000129961 SCV000687508 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-05 criteria provided, single submitter clinical testing

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