ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.7740A>C (p.Arg2580Ser) (rs199915459)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589821 SCV000149163 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.7740A>C at the cDNA level, p.Arg2580Ser (R2580S) at the protein level, and results in the change of an Arginine to a Serine (AGA>AGC). This variant has been observed in individuals with breast or ovarian cancer (Lu 2015, Tung 2016). ATM Arg2580Ser was observed at an allele frequency of 0.03% (11/34,414) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Arg2580Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115254 SCV000186651 likely benign Hereditary cancer-predisposing syndrome 2018-08-16 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;Subpopulation frequency in support of benign classification
Invitae RCV000205594 SCV000261019 benign Ataxia-telangiectasia syndrome 2020-12-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855570 SCV000694357 likely benign not specified 2020-10-05 criteria provided, single submitter clinical testing Variant summary: ATM c.7740A>C (p.Arg2580Ser) 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 0.0003 in 143322 control chromosomes, predominantly at a frequency of 0.0021 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2 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 Latino origin. c.7740A>C has been reported in the literature in individuals affected with breast cancer, ovarian cancer and Chronic Lymphocytic Leukemia patients (Tung_2016, Lu_2015, Tiao_2017, Dutil_2019, Tsaousis_2019, Da Costa_2020). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (4x) and likely benign (3x). Based on the evidence outlined above, the variant was classified as likely benign.
GeneKor MSA RCV000115254 SCV000821873 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000205594 SCV000838596 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000589821 SCV000840963 uncertain significance not provided 2018-06-29 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115254 SCV000902816 likely benign Hereditary cancer-predisposing syndrome 2016-10-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589821 SCV001469959 uncertain significance not provided 2020-07-28 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.