ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7880A>G (p.Tyr2627Cys) (rs767670019)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567581 SCV000660630 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000204776 SCV000260313 uncertain significance Ataxia-telangiectasia syndrome 2018-12-08 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 2627 of the ATM protein (p.Tyr2627Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual affected with lung squamous cell carinoma(PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 220064). 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. A different missense substitution at this codon (p.Tyr2627Cys) has been determined to be pathogenic (PMID: 22071889). This suggests that the tyrosine residue is critical for ATM protein function and that other missense substitutions at this position may also be pathogenic. 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 RCV000204776 SCV000838602 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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