ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6176C>T (p.Thr2059Ile) (rs144761622)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588663 SCV000149135 likely benign not provided 2021-06-05 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28135145, 27443514, 25186627, 19781682, 12917204, 17333338, 17517479, 20305132, 17623063, 23555315)
Ambry Genetics RCV000115226 SCV000186819 likely benign Hereditary cancer-predisposing syndrome 2019-07-08 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Insufficient evidence;Other strong data supporting benign classification
Invitae RCV000196722 SCV000252969 benign Ataxia-telangiectasia syndrome 2020-12-08 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212040 SCV000593505 uncertain significance not specified 2016-09-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212040 SCV000694319 benign not specified 2021-06-21 criteria provided, single submitter clinical testing Variant summary: ATM c.6176C>T (p.Thr2059Ile) results in a non-conservative amino acid change located in the PIK-related kinase (IPR014009) of 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 0.00023 in 251306 control chromosomes, predominantly at a frequency of 0.0033 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Consistently, this variant is observed at a frequency of 22/9884 subjects to include 21 women of African American ancestry (0.002226) in the FLOSSIES database of cancer free women at age 70. c.6176C>T has been reported in the literature in settings of multgene cancer panel testing in controls as well as patients with a variety of cancers to include breast, colorectal, endometrial and therapy related myeloid neoplasms without strong evidence for pathogenicity (example, Ho_2007, Edvardsen_2007, Bretsky_2003, Hirsch_2008, Bernstein_2010, Ring_2016, Yurgelun_2017, Tung_2015, Singhal_2021). This variant was reported as a germline VUS to co-occur with a WT1 variant of somatic origin (c.1137dup, p.R380Tfs*5) in one case of therapy related myeloid neoplasm (Singhal_2021). At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.5042_5043delTG, p.Val1681fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=3; VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation and at-least one additional submitter has re-classified this variant from a VUS to likely benign since its previous evaluation. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics,PreventionGenetics RCV000588663 SCV000805596 uncertain significance not provided 2016-08-02 criteria provided, single submitter clinical testing
Mendelics RCV000196722 SCV000838567 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115226 SCV000902666 likely benign Hereditary cancer-predisposing syndrome 2015-09-23 criteria provided, single submitter clinical testing
Baylor Genetics RCV000196722 SCV001481632 uncertain significance Ataxia-telangiectasia syndrome 2019-10-08 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Natera, Inc. RCV000196722 SCV001466201 uncertain significance Ataxia-telangiectasia syndrome 2020-04-03 no assertion criteria provided clinical testing

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