ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2159G>A (p.Arg720His) (rs55830714)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211974 SCV000209695 uncertain significance not provided 2018-08-07 criteria provided, single submitter clinical testing This variant is denoted ATM c.2159G>A at the cDNA level, p.Arg720His (R720H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has been observed in at least one individual with breast cancer (Decker 2017). ATM Arg720His was observed at an allele frequency of 0.03% (5/18,772) in individuals of East Asian 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 Arg720His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159689 SCV000217564 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000205354 SCV000261508 uncertain significance Ataxia-telangiectasia syndrome 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 720 of the ATM protein (p.Arg720His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs55830714, ExAC 0.02%). This variant has been observed in individuals with breast cancer (PMID: 30287823, Invitae). However, in one of these individuals pathogenic allele[s] were also identified in ATM, which suggests that this c.2159G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 181924). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000159689 SCV000682032 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-09 criteria provided, single submitter clinical testing
Mendelics RCV000205354 SCV001138469 uncertain significance Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030522 SCV001193470 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV001174912 SCV001338345 uncertain significance not specified 2020-02-10 criteria provided, single submitter clinical testing Variant summary: ATM c.2159G>A (p.Arg720His) 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 0.0002 in 298502 control chromosomes (gnomAD and literature). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0002 vs 0.001), allowing no conclusion about variant significance. c.2159G>A has been reported in the literature in individuals affected with Breast Cancer (e.g. Bernstein_2010, Momozawa_2018) but also controls (Momozawa_2018). 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. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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.