Submissions for variant NM_000051.4(ATM):c.378T>A (p.Asp126Glu)

gnomAD frequency: 0.06244  dbSNP: rs2234997

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130989	SCV000185911	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Eurofins Ntd Llc (ga)	RCV000116424	SCV000230839	benign	not specified	2015-02-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000116424	SCV000301664	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000383613	SCV000367020	benign	Ataxia-telangiectasia syndrome	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000383613	SCV000558347	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130989	SCV000576458	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130989	SCV000682161	benign	Hereditary cancer-predisposing syndrome	2014-11-12	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710670	SCV000840934	benign	not provided	2017-07-17	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000710670	SCV001157003	benign	not provided	2023-10-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000710670	SCV001842271	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18502988, 24728327, 27153395, 17333338, 17517479, 22529920, 12552566, 22071889)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798367	SCV002042150	benign	Breast and/or ovarian cancer	2021-05-26	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225335	SCV002504995	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000116424	SCV002760504	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498500	SCV002808361	benign	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-09-02	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315662	SCV004016014	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315662	SCV005083935	benign	Familial cancer of breast	2024-04-19	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Breakthrough Genomics, Breakthrough Genomics	RCV000710670	SCV005213494	likely benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000116424	SCV000084299	not provided	not specified	2013-09-19	no assertion provided	reference population
Genetic Services Laboratory, University of Chicago	RCV000116424	SCV000150349	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Natera, Inc.	RCV000383613	SCV001454829	benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354449	SCV001549067	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Asp126Glu variant was identified in 15 of 1440 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer (Broeks 2008, Gonzalez-Hormazabal 2008, Mangone 2015, Petereit 2013, Thorstenson 2001) and was present in 1 of 200 control chromosomes (frequency: 0.005) from healthy individuals (Mangone 2015). The variant was also identified in dbSNP (ID: rs2234997) as With other allele, ClinVar (classified as benign by Ambry Genetics, Emory Genetics, Prevention Genetics, Invitae; classified as likely benign by Illumina, IBRMDL, GSLUC), Cosmic (classified as neutral), MutDB (classified as Polymorphism), ATM-LOVD, databases. The variant was not identified in LOVD 3.0, databases. The variant was identified in control databases in 5588 (478 homozygous) of 276988 chromosomes at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 4785 of 24012 chromosomes (freq: 0.199), Ashkenazi Jewish* in 143 of 10146 chromosomes (freq: 0.014), Latino in 396 of 34384 chromosomes (freq: 0.012), Other in 71 of 6456 chromosomes (freq: 0.011). The p.Asp126 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant is located with the Telomere-length maintenance and DNA damage repair functional domain increasing the likelihood that it may have clinical significance. ATM D126E genotypes, had a mild effect on survival, but the differences did not reach the level of statistical significance (Li 2006). In addition, the variant lead to decreased DDR response and efficiency, which is associated with increased risk of developing lung cancer in African American women (Wallace 2014). 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	RCV000116424	SCV001906067	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000116424	SCV001924462	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000116424	SCV001952495	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000116424	SCV002035409	benign	not specified		no assertion criteria provided	clinical testing