ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3240C>A (p.Asp1080Glu) (rs149911447)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000470743 SCV000547070 uncertain significance Ataxia-telangiectasia syndrome 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 1080 of the ATM protein (p.Asp1080Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs149911447, ExAC 0.03%). This variant has been reported in an individual affected with breast cancer (PMID: 26976419), and in another individual affected with megakaryoblastic leukemia and mediastinal germ cell tumor (PMID: 24831771). ClinVar contains an entry for this variant (Variation ID: 407683). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000481741 SCV000566879 uncertain significance not provided 2018-01-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.3240C>A at the cDNA level, p.Asp1080Glu (D1080E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAA). This variant has been observed in at least one patient with breast cancer as well as in an individual with concurrent acute megakaryoblastic leukemia and a mediastinal germ cell tumor, and was absent from 400 control samples (Oshrine 2014, Tung 2016). ATM Asp1080Glu was observed at an allele frequency of 0.026% (4/15,300) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located within the region of interaction with beta-adaptin (Tavtigian 2009). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Asp1080Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000575167 SCV000665492 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Mendelics RCV000470743 SCV000838518 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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