ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6604T>G (p.Tyr2202Asp) (rs730881311)

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 RCV000766519 SCV000209630 uncertain significance not provided 2018-06-04 criteria provided, single submitter clinical testing This variant is denoted ATM c.6604T>G at the cDNA level, p.Tyr2202Asp (Y2202D) at the protein level, and results in the change of a Tyrosine to an Aspartic Acid (TAT>GAT). This variant was observed in an individual with breast cancer, as well as in and individual with chronic lymphocytic leukemia (Mansouri 2013, Hauke 2018). ATM Tyr2202Asp was not observed at a significant frequency in large population cohorts (Lek 2016). Since Tyrosine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Tyr2202Asp is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether ATM Tyr2202Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159641 SCV000214861 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000199822 SCV000254133 uncertain significance Ataxia-telangiectasia syndrome 2018-12-15 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with aspartic acid at codon 2202 of the ATM protein (p.Tyr2202Asp). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is present in population databases (rs730881311, ExAC 0.01%). This variant has been reported in an individual with chronic lymphocytic leukemia (PMID: 24172824). ClinVar contains an entry for this variant (Variation ID: 181882). 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 disruptive, 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.
Genetic Services Laboratory, University of Chicago RCV000212047 SCV000593506 uncertain significance not specified 2016-10-06 criteria provided, single submitter clinical testing
Color RCV000159641 SCV000682356 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764938 SCV000896110 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212047 SCV000916575 uncertain significance not specified 2018-04-23 criteria provided, single submitter clinical testing Variant summary: ATM c.6604T>G (p.Tyr2202Asp) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 121096 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (1.7e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.6604T>G, has been reported in the literature in individuals affected with chronic lymphocytic leukemia and head and neck squamous cell carcinoma (Mansouri 2014, Lu 2015), however it also was found in women, older than age 70 years who have never had cancer (in the FLOSSIES database). 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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified 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.