ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7989_7991delTGT (p.Val2664del) (rs876660743)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214450 SCV000278410 likely pathogenic Hereditary cancer-predisposing syndrome 2015-09-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Deficient protein function by in vitro/ex vivo assay,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ,Other strong data supporting pathogenic classification
GeneDx RCV000478779 SCV000568335 uncertain significance not provided 2017-05-05 criteria provided, single submitter clinical testing This in-frame deletion of three nucleotides in ATM is denoted c.7989_7991delTGT at the cDNA level and p.Val2664del (V2664del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TTGT[delTGT]CCCT. This deletion occurs in a region that is conserved in mammals and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). This variant, also reported as c.7983_7991del (V2662del) by alternate nomenclature, has been reported in both the homozygous and compound heterozygous state in patients with Ataxia-telangiectasia, but with variable ATM protein expression levels in one study (Castellvi-Bel 1999, Sandoval 1999, Li 2000, Demuth 2011). Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider ATM Val2664del to be a variant of uncertain significance.
Invitae RCV000475820 SCV000546816 uncertain significance Ataxia-telangiectasia syndrome 2018-05-03 criteria provided, single submitter clinical testing This variant, c.7989_7991delTGT, results in the deletion of 1 amino acid(s) of the ATM protein (p.Val2664del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals with symptoms of ataxia-telangiectasia (A-T) as homozygous (PMID: 9887333) and compound heterozygous with another pathogenic ATM variant (PMID: 21965147), as well as in A-T-affected individuals in whom no second variant was reported (PMID: 10425038, 10817650). This variant is also known as V2662del, 7989delTGT and Del 3 at codon 2663 in the literature. ClinVar contains an entry for this variant (Variation ID: 233938). Experimental studies have shown that this in-frame deletion results in a protein that lacks detectable kinase activity and cannot protect cells from chromosomal breaks induced by ionizing radiation, but rescues the ionizing radiation hypersensitivity phenotype of an ATM loss-of-function cell line (PMID: 11805335). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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