ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8327T>C (p.Ile2776Thr) (rs746475628)

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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 RCV000217725 SCV000273038 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000217725 SCV000904751 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing
GeneDx RCV000478838 SCV000564668 uncertain significance not provided 2018-12-12 criteria provided, single submitter clinical testing This variant is denoted ATM c.8327T>C at the cDNA level, p.Ile2776Thr (I2776T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant was observed in an individual with a personal and family history of colorectal cancer and in at least two individuals with breast cancer (Esteban-Jurado 2015, Decker 2017, Yehia 2018). ATM Ile2776Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in kinase 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 Ile2776Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000229175 SCV000283079 uncertain significance Ataxia-telangiectasia syndrome 2018-09-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 2776 of the ATM protein (p.Ile2776Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs746475628, ExAC 0.004%). This variant has been reported in one of two individuals with colorectal cancer from a single family (PMID: 25058500). ClinVar contains an entry for this variant (Variation ID: 229723). 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. 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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