ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.76G>C (p.Glu26Gln) (rs730881361)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656754 SCV000209723 uncertain significance not provided 2017-06-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.76G>C at the cDNA level, p.Glu26Gln (E26Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAA>CAA). This variant was observed in an individual with endometrial cancer undergoing multi-gene hereditary cancer panel testing (Ring 2016). ATM Glu26Gln was not observed in large population cohorts (Lek 2016). Since Glutamic Acid and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Glu26Gln occurs at a position that is conserved in mammals and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Glu26Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000215116 SCV000277995 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000465732 SCV000546863 uncertain significance Ataxia-telangiectasia syndrome 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 26 of the ATM protein (p.Glu26Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 181944). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000159711 SCV000602572 uncertain significance not specified 2017-04-07 criteria provided, single submitter clinical testing
Color RCV000215116 SCV000682431 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000159711 SCV001362597 uncertain significance not specified 2019-01-30 criteria provided, single submitter clinical testing Variant summary: ATM c.76G>C (p.Glu26Gln) results in a conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 277066 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.76G>C has been reported in the literature in individuals affected with endometrial cancer and chronic lymphocytic leukemia (Tiao_2017, Ring_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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