ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.7313C>T (p.Thr2438Ile) (rs147604227)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589408 SCV000149155 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.7313C>T at the cDNA level, p.Thr2438Ile (T2438I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has been reported as neutral based on the fact that it was found to occur in cis with a truncating variant in a patient with Ataxia-telangiectasia (Li 2000). ATM Thr2438Ile was also reported in at least two individuals undergoing multigene cancer panel testing based on a history of early-onset breast cancer or a Lynch-syndrome associated cancer and/or polyps (Maxwell 2014, Yurgelun 2015). Hirsch et al. (2008) did not identify this variant in a series of 31 breast cancer cases of African American ancestry, but did observe it in 1/95 age- and population-matched controls, and Decker et al. (2017) observed this variant in 1/13,087 breast cancer cases and 0/5,488 controls from the United Kingdom. This variant was also observed in a multi-ethnic breast cancer case/control study in which no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Thr2438Ile was observed at an allele frequency of 0.20% (47/24,004) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the FAT domain (Stracker 2013). 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 Thr2438Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115246 SCV000186496 likely benign Hereditary cancer-predisposing syndrome 2019-02-11 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign) ;No disease association in appropriately sized case-control study(ies);Other data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae RCV000200256 SCV000254142 likely benign Ataxia-telangiectasia syndrome 2020-11-26 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000115246 SCV000576463 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515201 SCV000611370 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260260 SCV000694348 likely benign not specified 2020-09-25 criteria provided, single submitter clinical testing Variant summary: ATM c.7313C>T (p.Thr2438Ile) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 329982 control chromosomes, predominantly at a frequency of 0.002 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 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 African or African-American origin. c.7313C>T has been reported in the literature in sequencing studies of individuals with varied indications such as, an individual with Ataxia Telangiectasia (Li_2000), as not associated with risk of breast cancer in an array GWAS study of a multiethnic population (Haiman_2013), unaffected controls of African American and Japanese ancestry (Hirsch_2008, Momozawa_2018), a patient with a clinical indication of Lynch syndrome associated cancer and/or polyps undergoing multigene panel testing (Yurgelun_2015), and a patient with AML in the TGCA cohort (Lu_2015). These reports however, do not provide unequivocal conclusions about association of the variant with Breast Cancer. Additionally, the variant was found to occur in ten African American women who are older than 70 years of age and cancer free as reported in the FLOSSIES database. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=3) or uncertain significance (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000200256 SCV000838591 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000589408 SCV000861415 uncertain significance not provided 2018-06-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115246 SCV000902700 benign Hereditary cancer-predisposing syndrome 2015-09-08 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354272 SCV001548846 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Thr2438Ile variant was identified in 6 of 43,426 proband chromosomes (frequency: 0.0001) from individuals or families with ataxia telangiectasia, Lynch Syndrome, or breast cancer and was present in 4 of 58,628 control chromosomes (frequency: 0.00006) from healthy individuals (Momozawa 2018, Hirsch 2008, Decker 2017, Yurgelun 2015, Maxwell 2015). The variant was identified in dbSNP (rs147604227) as “with uncertain significance, other allele”, ClinVar (classified as uncertain significance by Integrated Genetics, GeneDx, Eurofins and 3 other submitters; as likely benign by Invitae and Ambry Genetics; and as benign by Color) and LOVD 3.0 (observed 3x). The variant was identified in control databases in 55 of 282,330 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 50 of 24,936 chromosomes (freq: 0.002) and Latino in 5 of 35,420 chromosomes (freq: 0.0001), while it was not observed in the Ashkenazi Jewish, East Asian, Finnish, European, Other or South Asian populations. The variant was observed in an ataxia telangiectasia patient in cis with a pathogenic ATM variant (Li 2000), decreasing the likelihood that this variant has clinical significance. The p.Thr2438 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.