ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8393C>A (p.Ala2798Asp) (rs772992098)

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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 RCV000218858 SCV000274338 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000218858 SCV000687826 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing
GeneDx RCV000484197 SCV000564670 uncertain significance not provided 2017-12-29 criteria provided, single submitter clinical testing This variant is denoted ATM c.8393C>A at the cDNA level, p.Ala2798Asp (A2798D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCC>GAC). This variant has been reported in at least three individuals with breast cancer and one with lung squamous cell carcinoma (Lu 2015, Talukder 2015). ATM Ala2798Asp was not observed in large population cohorts (Lek 2016). This variant is located in the Kinase domain (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Ala2798Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204614 SCV000261291 uncertain significance Ataxia-telangiectasia syndrome 2018-12-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 2798 of the ATM protein (p.Ala2798Asp). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs772992098, ExAC 0.001%). This variant has been reported in an individual affected with lung cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 220614). 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 tolerated, 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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