ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7308A>C (p.Arg2436Ser) (rs730881317)

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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 RCV000159650 SCV000274643 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000212062 SCV000209640 uncertain significance not provided 2018-07-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.7308A>C at the cDNA level, p.Arg2436Ser (R2436S) at the protein level, and results in the change of an Arginine to a Serine (AGA>AGC). This variant was observed in an individual with ovarian cancer (Shirts 2016). ATM Arg2436Ser was not observed in large population cohorts (Lek 2016). This variant is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg2436Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000555685 SCV000622732 uncertain significance Ataxia-telangiectasia syndrome 2018-08-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 2436 of the ATM protein (p.Arg2436Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant also falls at the first nucleotide of exon 50 of the ATM coding sequence. This variant is not present in population databases (rs730881317, ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 181890). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine,University of Washington RCV000159650 SCV000266149 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing

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