ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4279G>A (p.Ala1427Thr) (rs2229021)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130581 SCV000185453 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000130581 SCV000911024 likely benign Hereditary cancer-predisposing syndrome 2016-06-21 criteria provided, single submitter clinical testing
Counsyl RCV000467455 SCV000792232 uncertain significance Ataxia-telangiectasia syndrome 2017-06-13 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000222514 SCV000859746 uncertain significance not provided 2018-03-04 criteria provided, single submitter clinical testing
GeneDx RCV000222514 SCV000278825 uncertain significance not provided 2017-11-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.4279G>A at the cDNA level, p.Ala1427Thr (A1427T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). This variant has been observed in at least two individuals with breast cancer (Hirsch 2008, Tavtigian 2009). ATM Ala1427Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ala1427Thr is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Ala1427Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000467455 SCV000546875 uncertain significance Ataxia-telangiectasia syndrome 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1427 of the ATM protein (p.Ala1427Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs2229021, ExAC 0.02%). This variant has been reported in individuals affected with breast cancer (PMID: 17333338, 19781682). ClinVar contains an entry for this variant (Variation ID: 141884). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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