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 The c.5320-5_5320-2delTCTA (also known as IVS37-5delTCTA) intronic pathogenic mutation, located upstream of coding exon 35 in the ATM gene, results from a deletion of 4 nucleotides at positions c.5320-5 to c.5320-2. This mutation (designated as 5320del7) has been observed in multiple individuals with a diagnosis of ataxia-telangiectasia (A-T) (Gilad S et al, Hum. Mol. Genet. 1996 Apr; 5(4):433-9, Eng L et al, Hum. Mutat. 2004 Jan; 23(1):67-76). A-T individuals with at least one copy of this mutation are reported to have no detectable ATM protein (Eng L et al, Hum. Mutat. 2004 Jan; 23(1):67-76). The c.5320-5_5320-2delTCTA mutation has also been reported to cause aberrant splicing that results in the removal of 7 coding nucleotides from coding exon 35, and a transcript that is expected to trigger nonsense-mediated mRNA decay (Eng L et al, Hum. Mutat. 2004 Jan; 23(1):67-76). RNA studies have demonstrated that this alteration results in the same aberrant splicing event reported in the literature (Ambry internal data). Based on the supporting evidence, this alteration is classified as a pathogenic mutation.
Invitae RCV000232019 SCV000282988 pathogenic Ataxia-telangiectasia syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 35 of the ATM gene. RNA analysis indicates that this variant induces altered splicing and may result 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). This variant is also known as IVS37-5delTCTA or c.5320del7 in the literature. ClinVar contains an entry for this variant (Variation ID: 181881). Studies have shown that this variant is associated with deletion of the first seven nucleotides of exon 36 (also known as exon 38), which introduces a frameshift (PMID: 14695534). The resulting mRNA is expected to undergo nonsense-mediated decay. 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 Health, Inc RCV000159640 SCV001347420 pathogenic Hereditary cancer-predisposing syndrome 2019-12-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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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