ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6998C>A (p.Thr2333Lys) (rs150503164)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212056 SCV000149148 uncertain significance not provided 2018-11-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.6998C>A at the cDNA level, p.Thr2333Lys (T2333K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). ATM Thr2333Lys has been observed in an individual reported to have Ataxia-telangiectasia who was found to harbor two additional ATM variants; phase was not reported (Micol 2011). In addition, this variant was reported in at least one individual with pancreatic cancer, but also in a control individual in a breast cancer case-control meta-analysis (Tavtigian 2009, Puri 2014). ATM Thr2333Lys was observed at an allele frequency of 0.125% (30/24026) in individuals of African ancestry in large population cohorts (Lek 2016). ATM Thr2333Lys is located in the FAT domain (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Thr2333Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115239 SCV000185041 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-03 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV001079437 SCV000254140 likely benign Ataxia-telangiectasia syndrome 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000115239 SCV000910893 likely benign Hereditary cancer-predisposing syndrome 2015-10-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001201251 SCV001372353 likely benign not specified 2020-06-08 criteria provided, single submitter clinical testing Variant summary: ATM c.6998C>A (p.Thr2333Lys) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 251024 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.6998C>A has been reported in the literature in individuals affected with Breast Cancer as well as in settings of multigene panel testing (example, Tung_2015, Young_2016). Additionally, this variant has also been reported in at-least one patient with Ataxia Telangiectasia (AT) who was compound heterozygous for two other deletrious variants in the ATM gene (Micol_2011). Although the phase of this variant relative to either of the deleterious variants was not provided, this finding supports a benign impact for this variant. Taken together, these report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer or with AT. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2, VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign.

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