ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6974C>T (p.Ala2325Val) (rs200940211)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212052 SCV000149145 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing This variant is denoted ATM c.6974C>T at the cDNA level, p.Ala2325Val (A2325V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). This variant has been observed in at least two individuals with breast cancer and another with a Lynch syndrome-associated cancer and/or polyps (Lu 2015, Yurgelun 2015, Tung 2015). ATM Ala2325Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the FAT 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 Ala2325Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000122881 SCV000166139 uncertain significance Ataxia-telangiectasia syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 2325 of the ATM protein (p.Ala2325Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs200940211, ExAC 0.006%). This variant has been reported in an individual undergoing Lynch syndrome testing (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127431). 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.
Ambry Genetics RCV000115236 SCV000218222 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000115236 SCV000682378 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-16 criteria provided, single submitter clinical testing
Mendelics RCV000122881 SCV000838585 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000115236 SCV000787879 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-01 no assertion criteria provided clinical testing

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