ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5089A>G (p.Thr1697Ala) (rs142455912)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212027 SCV000149114 uncertain significance not provided 2021-03-23 criteria provided, single submitter clinical testing Published functional studies suggest no damaging effect: lymphoblastoid cell line showed normal constitutive ATM protein level (Angele 2003) In silico analysis supports that this missense variant does not alter protein structure/function Not observed at a significant frequency in large population cohorts (Lek 2016) This variant is associated with the following publications: (PMID: 33395407, 12473594, 30972172, 30979843, 28652578, 30197789, 28779002, 25186627, 28135145, 27150160, 19781682, 26689913, 26787654, 19683821, 26350204, 14695186)
Ambry Genetics RCV000115205 SCV000184397 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-24 criteria provided, single submitter clinical testing The p.T1697A variant (also known as c.5089A>G), located in coding exon 33 of the ATM gene, results from an A to G substitution at nucleotide position 5089. The threonine at codon 1697 is replaced by alanine, an amino acid with similar properties. This alteration has been detected in 3/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This alteration was reported in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J. Med. Genet., 2016 06;53:366-76). This alteration was also detected on a 25-gene panel test in a woman of Western/Northern European ancestry who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000200336 SCV000254119 likely benign Ataxia-telangiectasia syndrome 2020-12-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515379 SCV000611366 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212027 SCV000805578 uncertain significance not provided 2017-12-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115205 SCV000902827 likely benign Hereditary cancer-predisposing syndrome 2015-10-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779803 SCV000916607 uncertain significance not specified 2021-03-21 criteria provided, single submitter clinical testing Variant summary: ATM c.5089A>G (p.Thr1697Ala) results in a non-conservative amino acid change in 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 4.3e-05 in 254138 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.3e-05 vs 0.004), allowing no conclusion about variant significance. c.5089A>G has been reported in the literature in individuals affected with Hodgkins disease, breast cancer, colorectal cancer, lung adenocarcinoma, and CLL (Offit_2002, Angele_2003, Tavtigian_2009, Tung_2015, Lu_2015, Young_2015, Yurgelun_2017, Tiao_2017, Parry_2017). These reports however, do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or susceptibility to breast or other cancers. One publication reports experimental evidence showing that the cell lines from the breast cancer patient carrying c.5089A>G showed no differences in the constitutive ATM protein level (Angele_2003) although the authors did not provide any primary data substantiating this observation. Six other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354115 SCV001548649 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Thr1697Ala variant was identified in 4 of 5698 proband chromosomes (frequency: 0.0007) from individuals or families with breast cancer or Hodgkin’s Disease and was not identified in 624 control chromosomes from healthy individuals (Angele 2003, Offit 2002, Tavtigian 2009). The variant was also identified in dbSNP (ID: rs142455912) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, and one clinical laboratory). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 12 of 276948 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24030 chromosomes (freq: 0.00004), Latino in 1 of 34416 chromosomes (freq: 0.00003), European in 10 of 126462 chromosomes (freq: 0.00008), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr1697 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of 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.