ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5080G>A (p.Ala1694Thr) (rs756197350)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000462765 SCV000546963 uncertain significance Ataxia-telangiectasia syndrome 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1694 of the ATM protein (p.Ala1694Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs756197350, ExAC 0.003%). This variant has been reported in individuals affected with breast cancer and colorectal cancer (PMID: 25503501, 28135145). ClinVar contains an entry for this variant (Variation ID: 407631). 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. 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 RCV000481315 SCV000565854 uncertain significance not provided 2016-11-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.5080G>A at the cDNA level, p.Ala1694Thr (A1694T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant was observed in at least one individual diagnosed with breast cancer under the age of 40 undergoing multi-gene panel testing (Maxwell 2015). ATM Ala1694Thr 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 Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ala1694Thr occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Ala1694Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000583320 SCV000687606 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-16 criteria provided, single submitter clinical testing
Counsyl RCV000462765 SCV000790892 uncertain significance Ataxia-telangiectasia syndrome 2018-05-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV000583320 SCV001185402 likely benign Hereditary cancer-predisposing syndrome 2018-02-09 criteria provided, single submitter clinical testing Other strong data supporting benign classification

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