ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8786+1G>A (rs17174393)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115269 SCV000149178 pathogenic not provided 2017-10-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.8786+1G>A or IVS60+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 60 of the ATM gene. The variant, also reported as ATM c.8672del115 and IVS62+1G>A using alternate nomenclature and exon numbering, 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 has been reported in association with recessively inherited Ataxia-Telangiectasia (Wright 1996, Stankovic 1998, Telatar 1998, Teraoka 1999, Laake 2000, Li 2000, García-Pérez 2001, Buzin 2003, Reiman 2011), and is considered pathogenic.
Counsyl RCV000169303 SCV000220622 likely pathogenic Ataxia-telangiectasia syndrome 2014-08-22 criteria provided, single submitter literature only
Ambry Genetics RCV000220586 SCV000273800 pathogenic Hereditary cancer-predisposing syndrome 2018-12-20 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
Invitae RCV000169303 SCV000283091 pathogenic Ataxia-telangiectasia syndrome 2019-11-25 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 60 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 (rs17174393, ExAC 0.003%). This variant has been observed in individuals with ataxia-telangiectasia (PMID: 8808599, 10330348, 8659541, 10980530, 9463314, 11298136, 10817650, 21459046, 21792198), and individuals with a family history of breast cancer (PMID: 21445571). This variant is also known as IVS62+1G>A and c.8672del115 in the literature. ClinVar contains an entry for this variant (Variation ID: 127463). 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.
Color RCV000220586 SCV000682516 pathogenic Hereditary cancer-predisposing syndrome 2020-02-20 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000115269 SCV000805632 pathogenic not provided 2016-11-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763226 SCV000893858 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169303 SCV000918527 pathogenic Ataxia-telangiectasia syndrome 2018-03-26 criteria provided, single submitter clinical testing Variant summary: ATM c.8786+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. Multiple publications, Laake_2000 and Stankovic_1998, functionally assessed the variant and found it to affect mRNA splicing. The variant was observed with an allele frequency of 1.2e-05 in 246218 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (1.2e-05 vs 0.004), allowing no conclusion about variant significance. The variant, c.8786+1G>A, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Laake_2000, Stankovic_1998). These data indicate that the variant is very likely to be associated with disease. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000169303 SCV000328305 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761159 SCV000891075 pathogenic Malignant Glioma 2017-02-13 no assertion criteria provided clinical testing

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