ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8248_8268del (p.Leu2750_Lys2756del) (rs771146489)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486046 SCV000572336 uncertain significance not provided 2016-11-29 criteria provided, single submitter clinical testing This in-frame deletion of 21 nucleotides in ATM is denoted c.8248_8268del21 at the cDNA level and p.Leu2750_Lys2756del (L2750_K2756del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GAAA[del21]gtaa. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu2750_Lys2756del was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The deleted residues are either conserved, conserved by class, or conserved through mammals, and are located in the kinase domain (Stracker 2013). Multiple splicing models predict that this variant may destroy the natural splice donor site for intron 56 and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. 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 Leu2750_Lys2756del to be a variant of uncertain significance.
Invitae RCV000628063 SCV000748952 uncertain significance Ataxia-telangiectasia syndrome 2017-11-10 criteria provided, single submitter clinical testing This variant, c.8248_8268del results in the deletion of 7 amino acids of the ATM protein (p.Leu2750_Lys2756del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 422777). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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