ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122884 SCV000166142 pathogenic Ataxia-telangiectasia syndrome 2019-12-04 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 2014-09-02 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.7788G>A at the DNA level. Although the variant is silent at the coding level, preserving a Glutamic Acid at codon 2596, has been demonstrated to cause abnormal splicing, specifically skipping of exon 52 (Broeks 1998). This exon comprises a large part of the FAT functional domain, involved in stability of the protein (Stracker 2013). The nucleotide which is altered, a guanine (G) at base 7788, is the last nucleotide of exon 52 and is highly conserved across species (Stracker 2013). This mutation was identified in two Ataxia-Telangiectasia patients, once with a pathogenic variant, and once in a homozygous state (Broeks 1998). ATM 7788G>A was not observed in 1000 Genomes database, and not evaluated in Exome Sequencing Project. Based on the currently available information, we consider ATM 7788G>A to be pathogenic.The presence of
Ambry Genetics RCV000217179 SCV000275620 pathogenic Hereditary cancer-predisposing syndrome 2017-05-03 criteria provided, single submitter clinical testing Last nucleotide of exon;Last nucleotide of exon with predicted splicing impact in agreement;Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;Other strong data supporting pathogenic classification;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Moderate segregation with disease (at least 3 informative meioses) for rare diseases.;Rarity in general population databases (dbsnp, esp, 1000 genomes);Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)
Color 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
Integrated Genetics/Laboratory Corporation of America RCV001255554 SCV001432026 pathogenic breast cancer 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.

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