ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4324T>C (p.Tyr1442His) (rs201666889)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586538 SCV000149099 uncertain significance not provided 2021-03-16 criteria provided, single submitter clinical testing Observed in individuals with leukemia, breast, ovarian, and/or colorectal cancer, but also in unaffected controls (Broeks 2008, Tavtigian 2009, Knappskog 2012, Lu 2015, Maxwell 2016, Tung 2016, Tiao 2017, Yehia 2018, Jarhelle 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22420423, 26976419, 20346647, 17393301, 19781682, 26420498, 24172824, 21787400, 23555315, 26689913, 27153395, 27067391, 28652578, 25479140, 20305132, 17623063, 29684080, 30166531, 30197789, 30303537, 31882575)
Ambry Genetics RCV000115190 SCV000183990 benign Hereditary cancer-predisposing syndrome 2019-05-14 criteria provided, single submitter clinical testing Other strong data supporting benign classification;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Invitae RCV000168302 SCV000218983 likely benign Ataxia-telangiectasia syndrome 2020-12-06 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515173 SCV000611361 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115190 SCV000682195 likely benign Hereditary cancer-predisposing syndrome 2020-07-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855627 SCV000694275 uncertain significance not specified 2020-10-16 criteria provided, single submitter clinical testing Variant summary: ATM c.4324T>C (p.Tyr1442His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 255904 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00032 vs 0.001), allowing no conclusion about variant significance. The variant of interest has been reported in the literature in individuals affected with Breast Cancer (Bernstein_2010, Broeks_2008, Edvardsen_2007, Goldgar_2011, Grant_2015, Mucaki_2016, Tavtigian_2009, Maxwell_2016, Tung_2016, Girard_2019, Schubert_2019, Jarhelle_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Knappskog_2012). 11 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (9x), likely pathogenic (1x) and benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000168302 SCV000745125 uncertain significance Ataxia-telangiectasia syndrome 2017-06-15 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000168302 SCV000745814 uncertain significance Ataxia-telangiectasia syndrome 2016-09-07 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000586538 SCV000805559 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000586538 SCV000840939 uncertain significance not provided 2019-12-06 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586538 SCV001148420 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV001257491 SCV001434302 uncertain significance Familial cancer of breast 2020-04-09 criteria provided, single submitter clinical testing This variant has been reported in the literature in individuals with breast and/or ovarian cancer (Broecks 2008, Tavtigian 2009, Knappskog 2012, Lu 2015, Maxell 2016, Tung 2016). This variant has an overall allele frequency of 0.0003 in the Broad Institute gnomAD Browser (https://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. PP3
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586538 SCV001469351 uncertain significance not provided 2019-12-06 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000168302 SCV000732991 uncertain significance Ataxia-telangiectasia syndrome no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355810 SCV001550802 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Tyr1442His variant was identified in 7 of 11034 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer, and was not identified in 4798 control chromosomes from healthy individuals (Broeks 2008, Knappskog 2012, Maxwell 2016, Tavtigian 2009, Tung 2016). The variant was also identified in the following databases: dbSNP (ID: rs201666889) as With Uncertain significance allele, ClinVar (classified as uncertain significance by GeneDx, Invitae, Color Genomics and two clinical laboratories; classified as benign by Ambry Genetics), and LOVD 3.0 (VUS). The variant was not identified in the GeneInsight-COGR, Cosmic, or MutDB databases. The variant was identified in control databases in 82 of 276704 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 1 of 6442 chromosomes (freq: 0.000155), European Non-Finnish in 76 of 126378 chromosomes (freq: 0.001), European Finnish in 5 of 25776 chromosomes (freq: 0.0002); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Tyr1442 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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. This variant was observed in one individual from our lab with a co-occurring pathogenic variant in CHEK2, c.1100delC, increasing the likelihood this variant does not have clinical significance. 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.
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000586538 SCV001905921 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000586538 SCV001919994 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000586538 SCV001952350 uncertain significance not provided no assertion criteria provided clinical testing

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