ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8560C>T (p.Arg2854Cys) (rs201958469)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131002 SCV000185927 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000656765 SCV000209659 uncertain significance not provided 2018-07-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.8560C>T at the cDNA level, p.Arg2854Cys (R2854C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been observed in individuals with breast or colorectal cancer as well as in one individual undergoing multi-gene panel testing for a personal and/or family history of cancer (Paglia 2010, de Voer 2016, Cabanillas 2017, Decker 2017, Yurgelun 2017). ATM Arg2854Cys was observed at an allele frequency of 0.07% (8/11,528) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is located in the kinase domain (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg2854Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656765 SCV000231411 uncertain significance not provided 2015-03-30 criteria provided, single submitter clinical testing
Invitae RCV000656765 SCV000254156 likely benign not provided 2019-03-04 criteria provided, single submitter clinical testing
Color RCV000131002 SCV000537553 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-02 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000585658 SCV000693456 uncertain significance Familial cancer of breast 2017-08-07 criteria provided, single submitter clinical testing This missense variant in the ATM gene was identified in a female patient with breast cancer at 45 years, and a familial history of breast cancer: 2 maternal cousins, 2 maternal aunts, one maternal grand-mother and one paternal cousin.
PreventionGenetics,PreventionGenetics RCV000656765 SCV000805628 uncertain significance not provided 2015-05-27 criteria provided, single submitter clinical testing
GeneKor MSA RCV000131002 SCV000821880 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000199741 SCV000838618 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000656765 SCV000840965 uncertain significance not provided 2017-11-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779783 SCV000916576 uncertain significance not specified 2019-02-08 criteria provided, single submitter clinical testing Variant summary: ATM c.8560C>T (p.Arg2854Cys) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 122824 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00021 vs 0.001), allowing no conclusion about variant significance. c.8560C>T has been reported in the literature in individuals affected with Breast Cancer, CRC, ALL, or CLL. These reports however do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656765 SCV001148452 uncertain significance not provided 2019-04-01 criteria provided, single submitter clinical testing

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