ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8015A>C (p.Asp2672Ala) (rs763161651)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219117 SCV000275400 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000219117 SCV000682451 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
GeneDx RCV000479711 SCV000567216 uncertain significance not provided 2016-03-24 criteria provided, single submitter clinical testing This variant is denoted ATM c.8015A>C at the cDNA level and p.Asp2672Ala (D2672A) at the protein level, and results in the change of an Aspartic Acid to an Alanine (GAC>GCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Asp2672Ala 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. Since Aspartic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Asp2672Ala occurs at a position that is conserved across species and is not located in a known functional domain (Tavtigian 2009, Stracker 2013, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Asp2672Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000551886 SCV000622795 uncertain significance Ataxia-telangiectasia syndrome 2018-07-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 2672 of the ATM protein (p.Asp2672Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is present in population databases (rs763161651, ExAC 0.002%). This variant has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 231524). 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.

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