ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4424A>G (p.Tyr1475Cys) (rs34640941)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000590782 SCV000602575 likely benign not provided 2017-05-04 criteria provided, single submitter clinical testing The p.Tyr1475Cys variant (rs34640941) has not been reported association with ataxia telangiectasia in the medical literature or gene specific variation databases but has been reported to ClinVar (Variation ID: 127392). However, the p.Tyr1475Cys variant has been identified in numerous cancer sequencing cohorts in both case and controls (Fang 2003, Meier 2005, Sipahimalani 2007, Sommer 2003, Tavtigian 2009, Tommiska 2006 and Yurgelun 2015). In a large meta-analysis of breast cancer studies, Tavtigian et al. identified the p.Tyr1475Cys variant in 1/4112 breast cancer cases and 6/2399 controls. Based on these observations the p.Tyr1475Cys variant is likely to be benign.
Ambry Genetics RCV000115197 SCV000185929 likely benign Hereditary cancer-predisposing syndrome 2017-09-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Intact protein function observed in appropriate functional assay(s),Subpopulation frequency in support of benign classification
Color RCV000115197 SCV000910566 likely benign Hereditary cancer-predisposing syndrome 2014-12-29 criteria provided, single submitter clinical testing
Counsyl RCV000122849 SCV000799741 uncertain significance Ataxia-telangiectasia syndrome 2018-05-03 criteria provided, single submitter clinical testing
GeneDx RCV000212017 SCV000149106 likely benign not specified 2018-01-04 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000590782 SCV000694283 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing Variant summary: The ATM c.4424A>G (p.Tyr1475Cys) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 59/115352 control chromosomes at a frequency of 0.0005115, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). Multiple publications cite the variant in affected individuals with varying phenotypes: Breast Cancer, Ovarian Cancer, non-Hodgkin's lymphoma, Lynch Syndrome and thyroid tumor, although with limited information (ie, lack of co-occurrence and cosegregation). One internal sample carries the variant of interest and MSH2 c.1861C>T/p.R621* (presumed pathogenic). Multiple reputable clinical laboratories cite the variant with conflicting classifcations, "uncertain significance" or "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as VUS-possibly benign until additional information becomes available.
Invitae RCV000122849 SCV000166107 likely benign Ataxia-telangiectasia syndrome 2018-01-09 criteria provided, single submitter clinical testing
Mendelics RCV000122849 SCV000838542 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000590782 SCV000805565 uncertain significance not provided 2016-12-22 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000115197 SCV000805217 likely benign Hereditary cancer-predisposing syndrome 2018-04-26 no assertion criteria provided clinical testing

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