ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3998A>T (p.Asp1333Val) (rs746709782)

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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 RCV000218774 SCV000274879 uncertain significance Hereditary cancer-predisposing syndrome 2015-03-30 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000462777 SCV000546837 uncertain significance Ataxia-telangiectasia syndrome 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 1333 of the ATM protein (p.Asp1333Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs746709782, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 231126). 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 disruptive, 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.
Integrated Genetics/Laboratory Corporation of America RCV000586338 SCV000694269 uncertain significance not provided 2017-02-02 criteria provided, single submitter clinical testing Variant summary: The ATM c.3998A>T (p.Asp1333Val) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/119294 control chromosomes at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; 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.
Color RCV000218774 SCV000913935 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-04 criteria provided, single submitter clinical testing

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