ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6988C>G (p.Leu2330Val)

gnomAD frequency: 0.00075  dbSNP: rs148432863
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587802 SCV000149147 likely benign not provided 2021-05-07 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19781682, 12810666, 25980754, 11505391, 23555315)
Invitae RCV000122882 SCV000166140 benign Ataxia-telangiectasia syndrome 2021-12-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115238 SCV000172962 likely benign Hereditary cancer-predisposing syndrome 2020-09-09 criteria provided, single submitter clinical testing Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212054 SCV000694339 benign not specified 2020-09-25 criteria provided, single submitter clinical testing Variant summary: ATM c.6988C>G (p.Leu2330Val) results in a conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 250962 control chromosomes, predominantly at a frequency of 0.0026 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 2.6-fold of the estimated maximal expected allele frequency for a pathogenic variant (MPAF) in ATM causing Breast Cancer phenotype (0.001), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. In addition, the variant was reported in 17/ 2559 African American women (i.e. with an allele frequency of 0.0033), who were older than age 70, and have never had cancer (in the FLOSSIES database); this allele frequency is 3.3-fold higher than the MPAF (0.001), strongly suggesting that the variant is benign. c.6988C>G has been reported in the literature in individuals affected with breast cancer (Teraoka_2001, Tavtigian_2009, Bernstein_2010) and in one individual with Lynch syndrome-associated cancer and/or colorectal polyps (Yurgelun_2015), however without strong evidence for causality. Furthermore, no association with the disease was found for this variant in a large breast cancer case-control study (Haiman_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (2x) and likely benign (4x). Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000122882 SCV000838587 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Eurofins NTD LLC (GA) RCV000587802 SCV000855439 uncertain significance not provided 2017-07-20 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115238 SCV000902719 likely benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000587802 SCV001502097 likely benign not provided 2020-09-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000212054 SCV002070979 likely benign not specified 2021-05-26 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV002225325 SCV002504762 benign Hereditary breast ovarian cancer syndrome 2022-04-19 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000115238 SCV002536820 likely benign Hereditary cancer-predisposing syndrome 2020-07-07 criteria provided, single submitter curation
Natera, Inc. RCV000122882 SCV001452130 uncertain significance Ataxia-telangiectasia syndrome 2019-10-30 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000587802 SCV001744647 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000587802 SCV001808702 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000587802 SCV001926301 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000587802 SCV001980445 likely benign not provided no assertion criteria provided clinical testing

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