ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.901+1G>A (rs748840480)

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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 RCV000166407 SCV000217201 pathogenic Hereditary cancer-predisposing syndrome 2018-04-20 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000205735 SCV000260474 pathogenic Ataxia-telangiectasia syndrome 2019-11-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 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 (rs748840480, ExAC 0.03%). This variant has been observed in individuals affected with ataxia-telangiectasia. One of the individuals carried a second pathogenic ATM variant (PMID: 12815592), while in the other a second ATM variant was not identified (PMID: 18321536). This variant is also known as IVS9 +1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 186761). 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.
Fulgent Genetics,Fulgent Genetics RCV000515230 SCV000611170 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-18 criteria provided, single submitter clinical testing
Counsyl RCV000205735 SCV000799901 pathogenic Ataxia-telangiectasia syndrome 2018-05-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000205735 SCV000918578 pathogenic Ataxia-telangiectasia syndrome 2018-12-07 criteria provided, single submitter clinical testing Variant summary: ATM c.901+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. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.8e-05 in 271632 control chromosomes (gnomAD). The variant, c.901+1G>A, has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Mitui_2003, Micol_2011, Du_2008) and one ovarian cancer (Crawford_2017) where it was found together with the pathogenic variant PALB2 c.2167_2168delAT (p.Met723fsX21). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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