ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.3925G>A (p.Ala1309Thr) (rs149711770)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212006 SCV000149091 likely benign not specified 2017-12-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000122844 SCV000166102 benign Ataxia-telangiectasia syndrome 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115182 SCV000185953 likely benign Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing In silico models in agreement (benign);Sub-population frequency in support of benign classification (not ava blue, manual h-w)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000587234 SCV000228296 uncertain significance not provided 2014-11-20 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212006 SCV000593510 uncertain significance not specified 2017-03-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282157 SCV000602552 uncertain significance none provided 2020-01-05 criteria provided, single submitter clinical testing The p.Ala1309Thr variant has been previously identified in association with breast cancer (Broeks 2008) However, a meta-analysis including the samples from Broeks et al and other breast cancer cohorts, found the p.Ala1309Thr variant in cases and controls at similar frequencies (Tavtigian 2009). This variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.11 percent (identified on 14 out of 12998 chromosomes) and is listed in the Exome Aggregation Consortium Browser with an overall population frequency of 0.062 percent (identified on 75 out of 121298 chromosomes). The alanine at position 1309 is weakly conserved (considering 9 species, Alamut v.2.8.1) and computational analyses of the effects of the p.Ala1309Thr variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Ala1309Thr variant with certainty. Pathogenic variants in ATM are causative for ataxia-telangiectasia (MIM: 208900), and are inherited in autosomal recessive manner. This individual is at least a carrier of the p.Ala1309Thr variant. Deep intronic variants and variants in the untranslated region are not analyzed by this method, therefore, another pathogenic ATM variant cannot be ruled out. Classic ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia, telangiectases of the conjunctivae, frequent infections, sensitivity to ionizing radiation, and an increased risk for malignancy. Serum immunoglobulin deficiencies (decreased concentrations of IgA, IgG, with normal or elevated IgM), poor antibody response to pneumococcal polysaccharide vaccines, and T and B cell deficiencies are common in classic A-T.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212006 SCV000694267 benign not specified 2020-10-22 criteria provided, single submitter clinical testing Variant summary: ATM c.3925G>A (p.Ala1309Thr) 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 0.00069 in 282624 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency (MPAF) for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001). In addition, in certain European subpopulations the variant was observed with an even higher occurrence, e.g. in the North-western European control population it occurred with a frequency of 0.0019, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Additionally, the variant was reported in 17/ 2559 European American women (i.e. with an allele frequency of 0.0015), who were older than age 70, and have never had cancer (in the FLOSSIES database); the allele frequency in this cohort is 1.5-fold higher than the MPAF (0.001), further supporting a benign role for the variant. The variant, c.3925G>A, has been reported in the literature in multiple individuals affected with Breast Cancer and other tumor phenotypes (without strong evidence for causality), and was also reported in controls, including a Swiss, non-cancer related cohort, where the variant was observed with an allele frequency of 0.005 (Kraemer_2019). In a large case-control study combined with meta-analysis, the variant was not associated with an increased risk for breast cancer (Tavtigian_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 15 other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (7x), likely benign (5x) or benign (3x). Based on the evidence outlined above, the variant was classified as benign.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000122844 SCV000745124 likely benign Ataxia-telangiectasia syndrome 2014-12-12 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000587234 SCV000805543 likely benign not provided 2017-07-06 criteria provided, single submitter clinical testing
Mendelics RCV000122844 SCV000838528 likely benign Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768149 SCV000898528 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-06-08 criteria provided, single submitter clinical testing ATM NM_000051.3 exon 26 p.Ala1309Thr (c.3925G>A): This variant has been reported in the literature in 1 individual with breast cancer (Dominguez-Valentin 2018 PMID:29371908). However, this variant is present in 0.1% (156/126510) of European alleles in the Genome Aggregation Database ( This variant is present in ClinVar (Variation ID:127377) with several conflicting entries between "variant of uncertain significance" and "likely benign". Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, the clinical significance of this variant is uncertain.
Color Health, Inc RCV000115182 SCV000902584 benign Hereditary cancer-predisposing syndrome 2016-03-15 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000587234 SCV001143106 benign not provided 2018-12-03 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587234 SCV001148417 uncertain significance not provided 2018-09-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000122844 SCV001262662 uncertain significance Ataxia-telangiectasia syndrome 2018-06-19 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Pittsburgh Clinical Genomics Laboratory,University of Pittsburgh Medical Center RCV001249851 SCV001424013 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-09 criteria provided, single submitter clinical testing This sequence variant is a single nucleotide substitution (G>A) that results in an alanine to threonine amino acid change at residue 1309 in the ATM protein. The variant is found at a frequency of 0.0062 (75/120390 alleles) in the Exome Aggregation Consortium database, with highest frequency among non-Finnish Europeans (0.00091, 61/66688 alleles). This residue (Ala1309) is not well conserved and is not found in a protein functional domain. In silico computational tools are inconclusive in their predictions on effects on protein structure and function. In a breast cancer case-control study (PMID: 19781682), the variant was found in 3/2531 cases and 3/2245 controls. These data indicate that this variant is not likely to be associated with disease, as it is found in equal frequencies in case and control populations. However, there is insufficient evidence to conclusively rule out any disease association. Thus, we consider this to be a variant of uncertain significance.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000122844 SCV001439180 likely benign Ataxia-telangiectasia syndrome 2020-08-19 criteria provided, single submitter clinical testing The ATM c.3925G>A (p.Ala1309Thr) missense variant has a frequency of 0.0006864 (194 of 282,624 alleles) in gnomAD v2.1.1 with a maximum frequency of 0.001209 (156 of 129,002) in the European non-Finnish subpopulation (BS1_Supporting, The most frequent known pathogenic variants in this gene occur at maximal subpopulation frequencies of 0.05%, 0.039%, and 0.033%. Five of seven in silico tools predict a benign effect of this variant on protein function (BP4; This variant has been observed in several patients with breast cancer (PMID: 26976419, 17393301, 20305132) and Lynch syndrome (PMID: 25980754). However, case control studies indicate that the variant is observed in equal frequencies in control individuals, suggesting that the variant is not likely to be associated with disease (PMID: 30287823, 19781682, 21787400). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1_Supporting, BP4.
Baylor Genetics RCV000122844 SCV001482828 uncertain significance Ataxia-telangiectasia syndrome 2019-01-20 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic RCV000587234 SCV001714398 uncertain significance not provided 2021-02-01 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000122844 SCV000745812 likely benign Ataxia-telangiectasia syndrome 2016-11-14 no assertion criteria provided clinical testing
True Health Diagnostics RCV000115182 SCV000787861 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355352 SCV001550220 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Ala1309Thr variant was identified in 15 of 138364 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer and was present in 3 of 30056 control chromosomes (frequency: 0.0001) from healthy individuals (Broeks 2008, Tavtigian 2009, Balmana 2016, Bernstein 2010, Goldgar 2011, Momozawa 2018, Tung 2016, Young 2016). The variant was also identified in dbSNP (ID: rs149711770) as "With other allele", ClinVar (classified as likely benign by Invitae, GeneDx, Ambry Genetics and five other submitters; and as uncertain significance by four submitters), and in LOVD 3.0 (3x as likely benign). The variant was identified in control databases in 191 of 276962 chromosomes at a frequency of 0.0007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 156 of 126510 chromosomes (freq: 0.001), African in 9 of 24028 chromosomes (freq: 0.0004), Other in 3 of 6460 chromosomes (freq: 0.0005), Latino in 6 of 34408 chromosomes (freq: 0.0002), East Asian in 15 of 18852 chromosomes (freq: 0.0008), Finnish in 2 of 25780 chromosomes (freq: 0.00008); it was not observed in the Ashkenazi Jewish or South Asian populations. This variant was identified by our laboratory in a patient with a co-occurring pathogenic BRIP1 variant (c.133G>T, p.Glu45*), increasing the likelihood that the ATM p.Ala1309Thr variant does not have clinical significance. The p.Ala1309 residue is not conserved in mammals and four out of five 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) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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