ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.655T>C (p.Cys219Arg) (rs771685059)

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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 RCV000574948 SCV000668117 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Color RCV000574948 SCV000904431 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780889 SCV000918521 uncertain significance not specified 2018-03-23 criteria provided, single submitter clinical testing Variant summary: ATM c.655T>C (p.Cys219Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was observed with an allele frequency of 8.1e-06 in 246000 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.1e-06 vs 4.00e-03), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.655T>C in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000627910 SCV000748794 uncertain significance Ataxia-telangiectasia syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 219 of the ATM protein (p.Cys219Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs771685059, 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: 482726). 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.
Mendelics RCV000627910 SCV000838474 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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