ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2630G>C (p.Ser877Thr) (rs370269552)

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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 RCV000115161 SCV000184961 likely benign Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),in silico models in agreement (benign)
Color RCV000115161 SCV000910866 benign Hereditary cancer-predisposing syndrome 2015-09-09 criteria provided, single submitter clinical testing
GeneDx RCV000211985 SCV000149070 uncertain significance not provided 2018-07-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.2630G>C at the cDNA level, p.Ser877Thr (S877T) at the protein level, and results in the change of a Serine to a Threonine (AGT>ACT). In a large meta-analysis by Tavtigian et al. (2009), this variant was reported at similar frequencies in breast cancer cases (3/2531) and controls (3/2245). ATM Ser877Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Ser877Thr 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 Ser877Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000168410 SCV000219104 uncertain significance Ataxia-telangiectasia syndrome 2018-05-12 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 877 of the ATM protein (p.Ser877Thr). The serine residue is weakly conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs370269552, ExAC 0.05%). This variant has been reported as homozygous in an individual affected with lung cancer (PMID: 26689913). In a large case-control study assessing the contribution of rare ATM missense variants with increased risk of breast cancer, this c.2630G>C variant showed no evidence for increased cancer risk (3/2,531 breast cancer cases versus 3/2,245 control individuals) (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 127356). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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