ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5009C>T (p.Ala1670Val) (rs375131360)

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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 RCV000561604 SCV000660480 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000561604 SCV000682242 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000115202 SCV000149111 uncertain significance not provided 2018-06-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.5009C>T at the cDNA level, p.Ala1670Val (A1670V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). This variant has been observed in at least one individual referred for hereditary cancer testing as well as in one unaffected control (Mu 2016, Tiao 2017). ATM Ala1670Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant 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 Ala1670Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000206394 SCV000261480 uncertain significance Ataxia-telangiectasia syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1670 of the ATM protein (p.Ala1670Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. 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: 127397). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably 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.

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