ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5320-5_5320-2del (rs730881310)

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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 RCV000159640 SCV000277203 pathogenic Hereditary cancer-predisposing syndrome 2019-06-24 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;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 RCV000232019 SCV000282988 pathogenic Ataxia-telangiectasia syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 35 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with ataxia-telangiectasia (PMID: 14695534, 8845835). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed in an individual with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 181881). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 14695534). 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.
Counsyl RCV000232019 SCV000678092 likely pathogenic Ataxia-telangiectasia syndrome 2017-03-08 criteria provided, single submitter clinical testing
Color RCV000159640 SCV001347420 pathogenic Hereditary cancer-predisposing syndrome 2019-12-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000232019 SCV001426884 pathogenic Ataxia-telangiectasia syndrome 2020-07-27 criteria provided, single submitter clinical testing Variant summary: ATM c.5320-5_5320-2delTCTA 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: Four predict the variant abolishes a 3' acceptor site. Four predict the variant creates a 3' acceptor site. The variant was absent in 249996 control chromosomes. c.5320-5_5320-2delTCTA has been reported in the literature in individuals affected with Ataxia-Telangiectasia or breast cancer (Gilad_1996, Eng_2004, Susswein_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Gilad_1996). 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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