ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7788G>A (p.Glu2596=) (rs587780639)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122884 SCV000166142 pathogenic Ataxia-telangiectasia syndrome 2020-09-25 criteria provided, single submitter clinical testing This sequence change affects codon 2596 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. It also falls at the last nucleotide of exon 52 of the ATM coding sequence. This variant is present in population databases (rs587780639, ExAC 0.002%). This variant has been reported in three individuals affected with ataxia telangiectasia; in two of these individuals this variant was observed in the homozygous state (PMID: 9792409, 26693373). ClinVar contains an entry for this variant (Variation ID: 135778). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies using protein truncation tests have shown that this variant can result in skipping of exon 52, also known as exon 54 in the literature (PMID: 9792409). If skipping of exon 52 occurs, it is expected to result in an in-frame deletion of 53 amino acid residues from the FAT domain of the ATM protein. The FAT domain is required for proper kinase activity of the ATM protein (PMID: 23532176, 25460276). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000159654 SCV000209647 pathogenic not provided 2019-11-18 criteria provided, single submitter clinical testing Alters the last nucleotide of the exon and is predicted to destroy the splice donor site, resulting in an in-frame deletion of exon 52, also known as exon 54 by alternate numbering, which has been confirmed with protein truncation testing (Broeks 1998); Observed with a pathogenic variant on the opposite allele (in trans) or in the homozygous state in unrelated patients with ataxia telangiectasia in the published literature (Broeks 1998, Aygun 2015); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 9792409, 25525159, 26681312, 26693373, 28126470, 32283892)
Ambry Genetics RCV000217179 SCV000275620 pathogenic Hereditary cancer-predisposing syndrome 2020-01-16 criteria provided, single submitter clinical testing The c.7788G>A pathogenic mutation (also known as p.E2596E), located in coding exon 51 of the ATM gene, results from a G to A substitution at nucleotide position 7788. This nucleotide substitution does not change the glutamic acid at codon 2596. However, this change occurs in the last base pair of coding exon 51, which makes it likely to have some effect on normal mRNA splicing. This mutation has been reported in multiple individuals with a clinical diagnosis of ataxia telangiectasia, two of whom were reported to be homozygous for the mutation (Broeks A et al. Hum. Mutat. 1998;12:330-7; Aygün FD et al. Case Rep Pediatr. 2015;2015: 615368). This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, and is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is insufficient at this time (Ambry internal data). Based on the available evidence, c.7788G>A is classified as a pathogenic mutation.
Color Health, Inc RCV000217179 SCV000682435 likely pathogenic Hereditary cancer-predisposing syndrome 2019-02-02 criteria provided, single submitter clinical testing
Counsyl RCV000122884 SCV000789712 likely pathogenic Ataxia-telangiectasia syndrome 2017-02-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001255554 SCV001432026 pathogenic Malignant tumor of breast 2020-08-26 criteria provided, single submitter clinical testing Variant summary: ATM c.7788G>A (p.Glu2596Glu) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. One predicts the variant weakens a 5 donor site. The variant allele was found at a frequency of 4e-06 in 250802 control chromosomes (gnomAD). c.7788G>A has been reported in the literature in multiple individuals affected with ataxia-telangiectasia or ovarian cancer (Broeks_1998, Micol_2011, Aygun_2015, Arvai_2019). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant results in shortening ATM protein (skipping of exon 52) (Broeks_1998) and expected to result in in-frame deletion of the protein, comprising a large part of FAT domain involved in stability of the protein (Micol_2011, PMID: 23532176). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV000122884 SCV001462594 pathogenic Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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