ClinVar Miner

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

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Total submissions: 20
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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 benign Ataxia-telangiectasia syndrome 2020-12-04 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Health, Inc 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001281009 SCV001468412 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2020-03-16 criteria provided, single submitter clinical testing ATM NM_000051.3 exon 29 p.Tyr1475Cys (c.4424A>G): This variant has been reported in the literature as germline in at least 6 individuals with various types of cancer (breast, colon, lymphoma) (Sipahimalani 2007 PMID:17640065, Tavtigian 2009 PMID:19781682, Yurgelun 2015 PMID:19781682, Tung 2016 PMID:26976419, Pearlman 2017 PMID:27978560). However, this variant has also been identified in controls (Tavtigian 2009 PMID:19781682) and is present in 0.1% (26/25072) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-108160516-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:127392). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590782 SCV001469353 likely benign not provided 2019-12-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV000122849 SCV001530024 uncertain significance Ataxia-telangiectasia syndrome 2018-11-15 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Nilou-Genome Lab RCV000122849 SCV001716381 uncertain significance Ataxia-telangiectasia syndrome 2021-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000212017 SCV001879473 likely benign not specified 2021-03-19 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
Natera, Inc. RCV000122849 SCV001462325 likely benign Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355381 SCV001550254 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Tyr1475Cys variant was identified in 4 of 1802 proband chromosomes (frequency: 0.002) from African-American, American, Finnish, Dutch and German individuals or families with breast cancer (unselected for history) or childhood acute lymphocytic leukemia; and was present in 1 of 856 control chromosomes (frequency: 0.001) from healthy individuals (Hirsch 2008, Tung 2016, Tommiska 2006, Meier 2005). The variant was also identified in the following databases: dbSNP (ID: rs34640941) “With Uncertain significance allele”, ClinVar (classified with conflicting interpretations of pathogenicity, sumbitters: uncertain significance by GeneDx; likely benign by Invitae and Ambry Genetics), Clinvitae (3x), Cosmic (1x in a diffuse large b cell lymphoma) and was not identified in the COGR, MutDB, LOVD 3.0 or ATM-LOVD databases. The variant was identified in control databases in 152 of 276060 chromosomes at a frequency of 0.0006 increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). It was identified in the following populations: African in 5 of 23840 chromosomes (frequency: 0002), Other in 4 of 6426 chromosomes (frequency: 0006), Latino in 10 of 34336 chromosomes (frequency: 0003), European Non-Finnish in 109 of 126152 chromosomes (frequency: 0.0009), and European Finnish in 24 of 25740 chromosomes (frequency: 005). The p.Tyr1475 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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