ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8921C>T (p.Pro2974Leu) (rs139379666)

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
Invitae RCV000122894 SCV000166152 benign Ataxia-telangiectasia syndrome 2020-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000200970 SCV000209668 uncertain significance not provided 2018-07-20 criteria provided, single submitter clinical testing This variant is denoted ATM c.8921C>T at the cDNA level, p.Pro2974Leu (P2974L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant was observed in individuals with breast cancer and in a child with acute lymphocytic leukemia (Oguchi 2003, Haiman 2013, Harismendy 2013). Functional assays performed by Oguchi et al. (2003) showed mRNA expression levels equivalent to wild type, partial rescue of the radiosensitive phenotype in fibroblasts, and reduction in phosphorylation activity; however, none of these assays showed complete loss of activity. ATM Pro2974Leu was observed at an allele frequency of 0.05% (9/18,866) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the FATC domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Pro2974Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159668 SCV000214151 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-27 criteria provided, single submitter clinical testing The p.P2974L variant (also known as c.8921C>T), located in coding exon 61 of the ATM gene, results from a C to T substitution at nucleotide position 8921. The proline at codon 2974 is replaced by leucine, an amino acid with similar properties. This variant was detected in a 1.5-year-old patient with acute lymphoblastic leukemia (Oguchi K et al. Blood. 2003 May;101:3622-7). Functional analysis performed by this same group showed an inability to rescue a radiosensitive phenotype, reduced kinase activity, and a possible dominant negative interference with the wild type allele. Another functional study showed decreased activity of homologous recombination-mediated double-strand break repair efficiency and also saw a dominant negative interference with the wild type allele (Guo X et al. Cancer Epidemiol. Biomarkers Prev., 2019 Aug;28:1308-1315). This alteration has been reported with a carrier frequency of 0.00766 in 7051 unselected breast cancer patients and 0.00783 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat. Commun. 2018 10;9:4083). This amino acid position is 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.
Counsyl RCV000122894 SCV000798159 uncertain significance Ataxia-telangiectasia syndrome 2018-02-28 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000200970 SCV000805634 uncertain significance not provided 2017-11-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000159668 SCV000910761 benign Hereditary cancer-predisposing syndrome 2016-06-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780903 SCV000918539 uncertain significance not specified 2021-06-12 criteria provided, single submitter clinical testing Variant summary: ATM c.8921C>T (p.Pro2974Leu) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) 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 8.2e-05 in 269470 control chromosomes (gnomAD and publication data). This frequency is not higher than the maximum expected for a pathogenic variant in ATM causing Breast Cancer (8.2e-05 vs 0.001). However, the variant was reported in some East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.0044 (in the jMorp database). This frequency is about 4.4 fold higher than the maximum expected for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), suggesting the variant could be a benign polymorphism. In addition, this variant has also been reported in 2/2559 African American women who were older than age 70 and cancer free (in the FLOSSIES database). c.8921C>T has been reported in the literature in individuals affected with Breast Cancer (BrC) and other tumor phenotypes. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. Two recent case-control association studies involving breast cancer patients and controls of Japanese ancestry found that the variant is not associated with a significant increase in breast/ovarian cancer risk, and therefore the authors of this study classified the variant as benign (Momozawa_2018, Fujita_2020). However, another recent case-control association study, involving breast cancer patients and controls of Chinese ancestry (Guo_2019), found an enrichment of this variant in cases, suggesting this variant could be associated with a risk for late onset BrC, though no statistically significant enrichment of this variant was observed in early-onset BrC patients (<45 years old). Publications also reported experimental evidence evaluating an impact on protein function, and in general these data suggest a partial loss of ATM activity (Oguchi_2003, Guo_2019). Due to a lack of complete loss of activity, the correlation of these findings to the in-vivo mechanism of disease remains unclear. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=6) and benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000122894 SCV001138587 uncertain significance Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030606 SCV001193491 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356215 SCV001551322 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Pro2974Leu variant was identified in 1 of 14 proband chromosomes (frequency: 0.07) from individuals or families with acute lymphoid and myeloid leukemia with mixed lineage leukemia (MLL) (Oguchi 2003). The variant was also identified in dbSNP (ID: rs139379666) as “With Uncertain significance allele”, in the ClinVar database as uncertain significance by Invitae, GeneDx, and Ambry Genetics. The variant was not identified in Cosmic, MutDB, LOVD 3.0, and ATM-LOVD databases. In addition, the variant was identified in control databases in 23 of 277148 chromosomes at a frequency of 0.00008 (Genome Aggregation Consortium Feb 27, 2017); in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and the NHLBI GO Exome Sequencing Project in 1 of 4402 African American alleles (frequency: 0.0002). In one functional study, the p.Pro2974Leu variant in the PI-3 kinase domain of the ATM gene was identified in one patient with myeloid leukemia with a normal level expression of the ATM protein. The variant leads to a change in the secondary structure of the ATM protein, namely, loss of random coil between alpha helices. In vitro kinase studies showed that 8921T was defective in mediating p53-Ser15 phosphorylation. Thus, this change in the secondary structure of the PI-3 kinase domain may disrupt its enzymatic function. Expression of 8921T ATM in AT fibroblasts sowed only partial rescue of the radiosensitive phenotype. In addition, its expression in U2OS cells showed an interfering effect with the normal function of ATM. This finding strongly suggests pathogenicity. Furthermore, segregation analysis revealed the father of the affected child to be heterozygous for the variant, thus excluding the possibility that the variant arising de novo in the patient. As of the writing of this study, the father remains disease free indicating a low penetrance. However, environmental factors such as exposure to top II inhibitors during development played a role in the development of MLL leukemia in this patient. The p.Pro2974 residue is conserved in mammals but not in more distantly related organisms 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, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Phosphatidylinositol 3-/4-kinase, catalytic domain Armadillo-type fold functional domain(s) increasing the likelihood that it may have clinical significance. 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.