ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.4424A>G (p.Tyr1475Cys) (rs34640941)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Invitae RCV000122849 SCV000166107 likely benign Ataxia-telangiectasia syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115197 SCV000185929 likely benign Hereditary cancer-predisposing syndrome 2018-10-02 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Subpopulation frequency in support of benign classification
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.
Integrated Genetics/Laboratory Corporation of America RCV000212017 SCV000694283 likely benign not specified 2019-04-25 criteria provided, single submitter clinical testing Variant summary: ATM c.4424A>G (p.Tyr1475Cys) results in a non-conservative amino acid change in 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 0.00061 in 252284 control chromosomes, predominantly within North-western European (at a frequency of 0.0014) and Finnish European (at a frequency of 0.0011) subpopulations in the gnomAD database (v2.1). These subpopulation frequencies are higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0014 and 0.0011 vs. 0.001), suggesting that the variant is a benign polymorphism found predominantly in European subpopulations. In addition, this variant has been reported in 16/7325 European American women (i.e. with an allele frequency of 0.0011), who are older than age 70 and cancer free (in the FLOSSIES database). Multiple publications cite the variant in affected individuals with varying tumor phenotypes, including breast-, pancreatic- and prostate cancer, lymphoma and Lynch Syndrome, although with limited information (i.e. lack of co-occurrence and cosegregation data). These reports therefore do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MSH2 c.1861C>T, p.Arg621X; in an internal sample), providing supporting evidence for a benign role. Furthermore, in a meta-analysis the variant was identified in 1/2531 breast cancer cases and 6/2245 controls (Tavtigian 2009). To our knowledge, no publication reported experimental evidence evaluating an impact on protein function. Eight other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (5x) or VUS (3x). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000122849 SCV000799741 uncertain significance Ataxia-telangiectasia syndrome 2018-05-03 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000590782 SCV000805565 uncertain significance not provided 2016-12-22 criteria provided, single submitter clinical testing
Mendelics RCV000122849 SCV000838542 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000115197 SCV000910566 likely benign Hereditary cancer-predisposing syndrome 2014-12-29 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000590782 SCV001148422 uncertain significance not provided 2016-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000122849 SCV001263904 uncertain significance Ataxia-telangiectasia syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Division of Medical Genetics, University of Washington RCV001250427 SCV001424785 uncertain significance Familial cancer of breast 2019-01-03 criteria provided, single submitter clinical testing This variant has been reported in individuals with breast cancer (Tung 2016, Tommiska 2006), as well as control populations (Hirsch 2008, Sommer 2003). The c.4424A>G variant has an overall allele frequency of 0.0006 in the Genome Aggregation Database (gnomad.broadinstitute.org). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk.
True Health Diagnostics RCV000115197 SCV000805217 likely benign Hereditary cancer-predisposing syndrome 2018-04-26 no assertion criteria provided clinical testing

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