ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2170G>A (p.Gly724Ser) (rs887317346)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000552619 SCV000622313 uncertain significance Ataxia-telangiectasia syndrome 2019-10-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 724 of the ATM protein (p.Gly724Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (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: 453406). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000566119 SCV000660787 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-12 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000566119 SCV000682034 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588042 SCV000694210 uncertain significance not specified 2019-09-20 criteria provided, single submitter clinical testing Variant summary: ATM c.2170G>A (p.Gly724Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251128 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2170G>A in individuals affected with Breast Cancer and no experimental evidence demonstrating an impact on protein function have been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (after 2014) and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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