ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.646G>T (p.Ala216Ser) (rs2235002)

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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 RCV000130381 SCV000185237 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-04 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000229944 SCV000283016 uncertain significance Ataxia-telangiectasia syndrome 2019-12-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 216 of the ATM protein (p.Ala216Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs2235002, ExAC 0.009%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 141750). 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.
GeneDx RCV000235636 SCV000293210 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.646G>T at the cDNA level, p.Ala216Ser (A216S) at the protein level, and results in the change of an Alanine to a Serine (GCT>TCT). While this variant was not observed in any of 4,112 breast cancer cases, it was observed in 1/2,399 control subjects in a meta-analysis study, and has also been reported in an individual with no obvious genetic disease as well as in an individual with acute myeloid leukemia (Thorstenson 2001, Tavtigian 2009, Lu 2015). ATM Ala216Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Ala216Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130381 SCV000682341 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-30 criteria provided, single submitter clinical testing

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