ClinVar Miner

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

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Total submissions: 10
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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 2019-09-09 criteria provided, single submitter clinical testing The p.K1269R variant (also known as c.3806A>G), located in coding exon 25 of the ATM gene, results from an A to G substitution at nucleotide position 3806. The lysine at codon 1269 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create an alternate splice donor site. RNA studies have demonstrated that this alteration does not result in significant levels of abnormal splicing in the set of samples tested (Ambry internal data). In addition, the in silico protein prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000206887 SCV000260024 uncertain significance Ataxia-telangiectasia syndrome 2020-11-02 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 been observed in individual(s) with breast cancer (PMID: 31811167). ClinVar contains an entry for this variant (Variation ID: 185981). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C2). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 31811167). 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 RCV000590439 SCV000564632 uncertain significance not provided 2021-05-05 criteria provided, single submitter clinical testing Observed in individuals with personal or family history of breast cancer (Decker 2017, Dominguez-Valentin 2019); Published functional studies suggest this variant may impact splicing resulting in several aberrant transcripts, but the effect was not complete as some full length transcript was also present in a mini gene assay (Dominguez-Valentin 2019); In silico analysis supports a deleterious effect on splicing; Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28779002, 31811167)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
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
Color Health, Inc RCV000165498 SCV000902910 likely benign Hereditary cancer-predisposing syndrome 2016-03-04 criteria provided, single submitter clinical testing
Natera, Inc. RCV000206887 SCV001458193 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000590439 SCV001742600 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000590439 SCV001954570 uncertain significance not provided no assertion criteria provided clinical testing

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