ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4709T>C (p.Val1570Ala) (rs140856217)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115199 SCV000183787 likely benign Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),In silico models in agreement (benign)
Color RCV000115199 SCV000902602 benign Hereditary cancer-predisposing syndrome 2016-08-08 criteria provided, single submitter clinical testing
Counsyl RCV000122851 SCV000792269 uncertain significance Ataxia-telangiectasia syndrome 2017-06-13 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000122851 SCV000745127 likely benign Ataxia-telangiectasia syndrome 2017-10-17 criteria provided, single submitter clinical testing
GeneDx RCV000586056 SCV000149108 uncertain significance not provided 2018-01-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.4709T>C at the cDNA level, p.Val1570Ala (V1570A) at the protein level, and results in the change of a Valine to an Alanine (GTT>GCT). This variant has been reported in several individuals with breast cancer, one with prostate cancer, and at least one with advanced cancer of unspecified type, as well as in an individual with a personal history of a Lynch syndrome-related cancer and/or polyps (Izatt 1999, Dork 2001, Pugh 2009, Tavtigian 2009, Yurgelun 2015, Maxwell, 2016, Tung 2016, Mandelker 2017). In one family, the variant was identified in both a proband with early onset breast cancer and her mother, who also had a history of breast cancer (Izatt 1999). ATM Val1570Ala was observed at an allele frequency of 0.07% (91/126,354) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Val1570Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000212021 SCV000593504 uncertain significance not specified 2016-10-18 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000122851 SCV000743729 likely benign Ataxia-telangiectasia syndrome 2014-10-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586056 SCV000694289 uncertain significance not provided 2017-07-28 criteria provided, single submitter clinical testing Variant summary: The ATM c.4709T>C (p.Val1570Ala) variant involves the alteration of a non-conserved nucleotide not located in any known functional domain (InterPro) and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant was found in 60/121794 control chromosomes at a frequency of 0.0004926, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). However, a combined frequency of all known 19 missense pathogenic ATM variants in ExAC cohort (9/120000) is less than the frequency of c.4709T>C alone, suggesting c.4709T>C is unlikely to associate with disease. In addition, despite relatively high frequency in control cohorts, the variant of interest has not been reported in Ataxia Telangiectasia patients. The variant of interest has been reported in cancer patients, but a causative role cannot be drawn from these occurrences since full phenotype, co-occurrence, nor cosegregation data was not provided. Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS) - possibly benign."
Invitae RCV000122851 SCV000166109 likely benign Ataxia-telangiectasia syndrome 2018-01-10 criteria provided, single submitter clinical testing
Mendelics RCV000122851 SCV000838544 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000586056 SCV000805570 uncertain significance not provided 2017-10-05 criteria provided, single submitter clinical testing

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