ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3265G>T (p.Ala1089Ser) (rs730881358)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215659 SCV000274769 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000215659 SCV000682112 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-06 criteria provided, single submitter clinical testing
GeneDx RCV000159708 SCV000209720 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.3265G>T at the cDNA level, p.Ala1089Ser (A1089S) at the protein level, and results in the change of an Alanine to a Serine (GCT>TCT). This variant was observed in breast cancer cases, as well as unaffected controls (Decker 2017). ATM Ala1089Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with beta-adaptin (Tavtigian 2009). 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 Ala1089Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779762 SCV000916539 uncertain significance not specified 2017-09-19 criteria provided, single submitter clinical testing Variant summary: The ATM c.3265G>T (p.Ala1089Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/276880 control chromosomes at a frequency of 0.0000108, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000228095 SCV000282927 uncertain significance Ataxia-telangiectasia syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 1089 of the ATM protein (p.Ala1089Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs730881358, ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181941). 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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