ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6475T>G (p.Cys2159Gly) (rs150408832)

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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 RCV000220825 SCV000274115 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000587154 SCV000616647 uncertain significance not provided 2017-07-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.6475T>G at the cDNA level, p.Cys2159Gly (C2159G) at the protein level, and results in the change of a Cysteine to a Glycine (TGT>GGT). This variant has been observed in a hepatosplenic T-cell lymphoma sample, but somatic status was not confirmed (McKinney 2017). ATM Cys2159Gly was observed at an allele frequency of 0.03% (3/10404) in individuals of African ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Cysteine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Cys2159Gly occurs at a position that is not conserved and is located in the FAT domain (Stracker 2013). Protein-based in silico analyses predict that this variant is probably damaging to protein structure and function, and multiple splicing models predict this variant may create a cryptic splice donor site and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether ATM Cys2159Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000554683 SCV000622669 uncertain significance Ataxia-telangiectasia syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 2159 of the ATM protein (p.Cys2159Gly). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and glycine. This variant is present in population databases (rs150408832, ExAC 0.03%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 230532). 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. 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.
Color RCV000220825 SCV000687706 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587154 SCV000694324 uncertain significance not provided 2015-10-16 criteria provided, single submitter clinical testing

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