ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7757A>G (p.Asn2586Ser) (rs587778079)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561937 SCV000660483 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000561937 SCV000903053 likely benign Hereditary cancer-predisposing syndrome 2017-04-04 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587034 SCV000335111 uncertain significance not provided 2015-09-29 criteria provided, single submitter clinical testing
GeneDx RCV000587034 SCV000209645 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing This variant is denoted ATM c.7757A>G at the cDNA level, p.Asn2586Ser (N2586S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). ATM Asn2586Ser was identified in 1/118 healthy Hispanic individuals undergoing whole genome sequencing (Bodian 2014); of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. ATM Asn2586Ser was observed at an allele frequency of 0.04% (14/34410) in individuals of Latino ancestry in large population cohorts (Lek 2016). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. ATM Asn2586Ser 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 Asn2586Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120158 SCV000084300 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000587034 SCV000694358 uncertain significance not provided 2017-06-16 criteria provided, single submitter clinical testing Variant summary: The ATM c.7757A>G (p.Asn2586Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution that does not lie within a known functional domain (InterPro). 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to non-functioning tool). This variant was found in the large control database ExAC at a frequency of 0.0000083 (1/120864 control chromosomes), 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 have classified this variant as one of uncertain significance. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been 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 RCV000465515 SCV000546946 uncertain significance Ataxia-telangiectasia syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 2586 of the ATM protein (p.Asn2586Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs587778079, ExAC 0.009%). This variant has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 133633). 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 serine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.

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