ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4138C>T (p.His1380Tyr) (rs3092856)

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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 RCV000128897 SCV000172757 benign Hereditary cancer-predisposing syndrome 2014-11-21 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.
PreventionGenetics,PreventionGenetics RCV000120137 SCV000301667 benign not specified criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120137 SCV000341032 benign not specified 2016-05-12 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000284881 SCV000367050 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.
Color Health, Inc RCV000128897 SCV000537385 benign Hereditary cancer-predisposing syndrome 2014-11-25 criteria provided, single submitter clinical testing
Invitae RCV000284881 SCV000558328 benign Ataxia-telangiectasia syndrome 2020-12-06 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000710672 SCV000840938 benign not provided 2017-09-05 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282151 SCV000883426 benign none provided 2020-06-05 criteria provided, single submitter clinical testing
GeneDx RCV000710672 SCV001894544 benign not provided 2015-03-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24728327, 27153395, 27016235, 11505391, 11746755, 22529920, 20981092, 22995991)
ITMI RCV000120137 SCV000084276 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000128897 SCV000787863 likely benign Hereditary cancer-predisposing syndrome 2017-11-14 no assertion criteria provided clinical testing
Natera, Inc. RCV000284881 SCV001458202 benign Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000710672 SCV001548778 likely benign not provided no assertion criteria provided clinical testing The ATM p.His1380Tyr variant was identified in 23 of 1184 proband chromosomes (frequency: 0.019) from individuals or families with CML, AML, ALL, Hodgkin disease and was present in 1 of 166 control chromosomes (frequency: 0.006) from healthy individuals (Melo 2001, Petereit 2013, Shi 2011, Takagi 2004). The variant was also identified in the following databases: dbSNP (ID: rs3092856) as other, ClinVar (classified as benign by Ambry Genetics, Prevention Genetics, Emory Genetics, Color Genomics, Invitae; classified as likely benign by Illumina), Cosmic (classified as Neutral (score 0.29), MutDB, and LOVD 3.0. The variant was not identified in the COGR, or ATM-LOVD. The variant was identified in control databases in 3636 (97 homozygous) of 277050 chromosomes at a frequency of 0.013 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 1625 of 24030 chromosomes (freq: 0.068), South Asian in 1484 of 30780 chromosomes (freq: 0.048), East Asian in 277 of 18862 chromosomes (freq: 0.015). The p.His1380 residue is not conserved in mammals and 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, HumanSpliceFinder) do not predict a difference in splicing. In study by Shi (2011), cases with ATM 4138CT variant presented with primary refractory disease, and ATM 4138C>T patients generally had inferior overall survival comparing with ATM 4138C>C patients. Results of a study by Takagi (2004) provide indirect evidence that H1380Y acts in a dominant-negative manner and H1380Y could be an allele with a very low penetrance. Patient with H1380Y exhibited normal p53 phosphorylation activity but defective c-Abl kinase activation. 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000120137 SCV001808968 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000120137 SCV001906174 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000710672 SCV001927293 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000120137 SCV001953117 benign not specified no assertion criteria provided clinical testing

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