ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6179G>C (p.Arg2060Pro) (rs376521407)

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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 RCV000221500 SCV000274556 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000459766 SCV000547100 uncertain significance Ataxia-telangiectasia syndrome 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 2060 of the ATM protein (p.Arg2060Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs376521407, 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: 230875). 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. 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.
GeneDx RCV000482223 SCV000564649 uncertain significance not provided 2017-08-22 criteria provided, single submitter clinical testing This variant is denoted ATM c.6179G>C at the cDNA level, p.Arg2060Pro (R2060P) at the protein level, and results in the change of an Arginine to a Proline (CGC>CCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Arg2060Pro was observed at an allele frequency of 0.03% (3/10,280) in individuals of African ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Arg2060Pro occurs at a position that is conserved across species and is located in the FAT domain (Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Arg2060Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000221500 SCV000906525 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779773 SCV000916563 uncertain significance not specified 2018-01-08 criteria provided, single submitter clinical testing Variant summary: The ATM c.6179G>C (p.Arg2060Pro) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 3/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 4/276988 control chromosomes (gnomAD) at a frequency of 0.0000144, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Other missense changes this residue (Arg2060Leu, Arg2060His and Arg2060Cys) have been classified as uncertain significance by clinical laboratories in ClinVar. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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