ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4375G>A (p.Gly1459Arg) (rs145667735)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115192 SCV000186391 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115192 SCV000682200 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515274 SCV000611362 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000586694 SCV000149101 uncertain significance not provided 2018-08-03 criteria provided, single submitter clinical testing This variant is denoted ATM c.4375G>A at the cDNA level, p.Gly1459Arg (G1459R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). ATM Gly1459Arg has been reported in several individuals with a history of cancer; five with breast cancer, one with colorectal cancer, and another with a Lynch syndrome-associated cancer and/or polyps (Edvardsen 2007, Yurgelun 2015, Tung 2016, Decker 2017, Dominguez-Valentin 2018). Additionally, this variant has been reported in comparable numbers among healthy controls and breast cancer cases in two case-control studies (Tavtigian 2009, Decker 2017). ATM Gly1459Arg was observed at an allele frequency of 0.012% (15/126,590) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Gly1459Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586694 SCV000694278 uncertain significance not provided 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The ATM c.4375G>A (p.Gly1459Arg) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 5/124364 control chromosomes at a frequency of 0.0000402, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant has been reported in breast cancer and Lynch syndrome patients in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000196015 SCV000254105 uncertain significance Ataxia-telangiectasia syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1459 of the ATM protein (p.Gly1459Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs145667735, ExAC 0.01%). This variant has been reported in the literature in individuals with breast cancer (PMID: 26976419, 17623063), colorectal cancer (PMID: 29458332), and in individuals undergoing Lynch syndrome testing (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127387). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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.
PreventionGenetics RCV000586694 SCV000805561 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing

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