ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.378T>A (p.Asp126Glu) (rs2234997)

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Total submissions: 17
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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: 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000116424 SCV000230839 benign not specified 2015-02-16 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000116424 SCV000301664 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
Invitae RCV000383613 SCV000558347 benign Ataxia-telangiectasia syndrome 2020-12-06 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 Health, Inc RCV000130989 SCV000682161 benign Hereditary cancer-predisposing syndrome 2014-11-12 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000710670 SCV000840934 benign not provided 2017-07-17 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283354 SCV001157003 benign none provided 2020-05-28 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)
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
Human Genetics - Radboudumc,Radboudumc RCV000116424 SCV001952495 benign not specified no assertion criteria provided clinical testing

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