ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000115192 SCV000186391 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000196015 SCV000254105 uncertain significance Ataxia-telangiectasia syndrome 2019-12-29 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 observed 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.
Fulgent Genetics,Fulgent Genetics RCV000515274 SCV000611362 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Color RCV000115192 SCV000682200 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing
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.
PreventionGenetics,PreventionGenetics RCV000586694 SCV000805561 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000586694 SCV001143109 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing
Pittsburgh Clinical Genomics Laboratory,University of Pittsburgh Medical Center RCV001249852 SCV001424014 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-19 criteria provided, single submitter clinical testing This sequence variant is a single nucleotide substitution (G>A) that results in a glycine to arginine amino acid change at residue 1459 in the ATM protein. This is a previously reported variant (ClinVar) that has been observed in at least one breast cancer patient (PMID 26976419), two patients being tested for Lynch syndrome (PMID 25980754), a patient with familial colorectal cancer (PMID 29458332), and one healthy control with no cancer (PMID 19781682). This variant is rare in control population datasets (gnomAD database, 16/276984 alleles, .006% overall frequency). A meta-analysis in breast cancer patients did not identify any enrichment of this variant in breast cancer cases versus healthy controls (PMID 19781682). The Gly1459 residue is not located in a known functional domain, and studies assessing the effect of this variant on ATM function are not published in the literature, to our knowledge. However, multiple in silico tools queried predict that this glycine to arginine amino acid change would be damaging. The glycine at this position is highly evolutionarily conserved across mammalian species examined. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider the significance of this variant to be uncertain.

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