ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3806A>G (p.Lys1269Arg) (rs146017595)

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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 RCV000165498 SCV000216229 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000165498 SCV000902910 likely benign Hereditary cancer-predisposing syndrome 2016-03-04 criteria provided, single submitter clinical testing
Counsyl RCV000206887 SCV000789440 uncertain significance Ataxia-telangiectasia syndrome 2017-02-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763700 SCV000894580 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000590439 SCV000564632 uncertain significance not provided 2017-12-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.3806A>G at the cDNA level, p.Lys1269Arg (K1269R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant was observed in two women with breast cancer and was absent from unaffected controls (Decker 2017). ATM Lys1269Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. While protein-based in-silico analysis supports that this variant does not alter protein structure/function, splicing models predict the creation of a novel splice donor site upstream of the natural splice donor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether ATM Lys1269Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590439 SCV000694266 uncertain significance not provided 2016-06-20 criteria provided, single submitter clinical testing Variant summary: The ATM c.3806A>G (p.Lys1269Arg) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 3/120788 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. It has been reported by two labs in ClinVar without evidence to independently evaluate and they have classified it as uncertain significance. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000206887 SCV000260024 uncertain significance Ataxia-telangiectasia syndrome 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 1269 of the ATM protein (p.Lys1269Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs146017595, ExAC 0.02%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 185981). 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 C25"). 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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