ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6315G>C (p.Arg2105Ser) (rs587780632)

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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 RCV000131258 SCV000186222 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000131258 SCV000537592 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
GeneDx RCV000589612 SCV000292472 uncertain significance not provided 2018-10-10 criteria provided, single submitter clinical testing This variant is denoted ATM c.6315G>C at the cDNA level, p.Arg2105Ser (R2105S) at the protein level, and results in the change of an Arginine to a Serine (AGG>AGC). This variant was observed in an individual with idiopathic ocular telangiectasias and has also been reported in individuals with breast cancer or a Lynch syndrome-associated cancer and/or polyps (Mauget-Fa?sse 2003, Tung 2015, Yurgelun 2015). ATM Arg2105Ser was observed at an allele frequency of 0.11% (11/9,842) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located within 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 Arg2105Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589612 SCV000694320 uncertain significance not provided 2016-02-15 criteria provided, single submitter clinical testing Variant summary: ATMc.6315G>C variant affects a conserved nucleotide, resulting in amino acid change from Arg to Ser. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have not been confirmed by experimental studies. This variant is found in 6/121496 control chromosomes at a frequency of 0.0000494, which does not significantly exceed maximal expected frequency of a pathogenic ATM allele (0.0039528). This variant has been reported in two patients, one with idiopathic juxtafoveolar retinal telangiectasia and one with LS. In addition, multiple clinical laboratories classified this variant as VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000122871 SCV000166129 uncertain significance Ataxia-telangiectasia syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 2105 of the ATM protein (p.Arg2105Ser). The arginine residue is highly  conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs587780632, ExAC 0.03%). This variant has been reported in an individual affected with idiopathic juxtafoveolar retinal telangiectasia (PMID: 12882767), and an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 135767). 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. 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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