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

gnomAD frequency: 0.00081  dbSNP: rs149711770

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV001762219	SCV002499290	benign	Familial cancer of breast	2022-03-09	reviewed by expert panel	curation	The ATM c.3925G>A (p.Ala1309Thr) variant has a GnomAD (v2.1.1) filtering allele frequency of 0.1050% (NFE) which is above the ATM BS1 threshold of .05% (BS1). This variant has been observed in a homozygous and compound heterozygous state in multiple individuals without ataxia-telangiectasia (Internal laboratory contributions; BP2_strong). Multiple in silico protein predictors predict that this alteration is not deleterious (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel.
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	2024-02-01	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	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago	RCV000212006	SCV000593510	likely benign	not specified	2021-01-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587234	SCV000602552	benign	not provided	2023-05-09	criteria provided, single submitter	clinical testing	The ATM c.3925G>A; p.Ala1309Thr variant (rs149711770) is reported in the literature in individuals affected with various cancers, but without clear disease association (Broeks 2008, Dominguez-Valentin 2018, Momozawa 2018, Xie 2018). This variant is also reported in equal numbers of cases and controls (Tavtigian 2009, Yu 2021), and in at least one family in which the variant did not segregate with disease (Wang 2019). This variant is also reported in ClinVar (Variation ID: 127377), and is found in the general population with an overall allele frequency of 0.069% (194/282624 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.076). Based on available information, this variant is considered to be benign.
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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000122844	SCV000745124	likely benign	Ataxia-telangiectasia syndrome	2014-12-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	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	RCV001762219	SCV000898528	benign	Familial cancer of breast	2023-12-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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 Center for Human Genetics Tuebingen	RCV000587234	SCV001148417	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	ATM: BP4
St. Jude Molecular Pathology, 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, https://gnomad.broadinstitute.org/). 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; https://pecan.stjude.cloud/variant/8471). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000587234	SCV001714398	likely benign	not provided	2023-05-03	criteria provided, single submitter	clinical testing	BS1, BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798315	SCV002042186	likely benign	Breast and/or ovarian cancer	2023-07-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115182	SCV002536662	likely benign	Hereditary cancer-predisposing syndrome	2021-07-20	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212006	SCV002760561	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000587234	SCV000228296	uncertain significance	not provided	2014-11-20	flagged submission	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	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	flagged submission	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV001249851	SCV001424013	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-03-09	flagged submission	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.
Baylor Genetics	RCV000122844	SCV001482828	uncertain significance	Ataxia-telangiectasia syndrome	2019-01-20	flagged submission	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000587234	SCV001905685	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000587234	SCV001919078	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587234	SCV001955945	likely benign	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000587234	SCV002029139	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 04-03-2019 by Lab or GTR ID Division of Clinical Laboratories Kingston General Hospital. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000587234	SCV002036169	likely benign	not provided		no assertion criteria provided	clinical testing