ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1744T>C (p.Phe582Leu) (rs2235006)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120118 SCV000149055 benign not specified 2017-06-08 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 RCV000122822 SCV000166079 benign Ataxia-telangiectasia syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115146 SCV000183793 benign Hereditary cancer-predisposing syndrome 2014-11-24 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 RCV000120118 SCV000225147 likely benign not specified 2015-03-20 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120118 SCV000301655 likely benign not specified criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120118 SCV000593498 likely benign not specified 2017-01-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115146 SCV000681996 likely benign Hereditary cancer-predisposing syndrome 2015-04-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588398 SCV000694196 likely benign not provided 2017-05-22 criteria provided, single submitter clinical testing Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a large size and aromatic Phenylalanine (F) with a medium size and hydrophobic Leucine (L). 4/4 in silico tools predict the variant to be neutral. It was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.098% which does not exceed the maximal expected allele frequency of a disease causing AT allele (0.4%). The variant was reported in CLL, ALL and breast cancer patients, however without information about family history and co-segregation, therefore these reports do not provide strong evidence for a casual impact of the variant. It was reported as a germline alteration in a patient with T-ALL associated with a t(11:14) translocation by cytogenetic analysis with no evidence of an allelic loss in tumor DNA. One publication suggest the variant to confer a risk for CLL (OR:11.23) based on a case control study, however, the significance of this finding is uncertain due to the OR being calculated based on only one affected patient (Rudd_Blood_2006). In other studies, reporting an OR for association with sporadic T-ALL, the 95% CI's overlapped 1.0, and had very small sample sizes, thereby providing little to no confidence in the assertion of the assertion. On study reported the variant to result in normal ATM protein levels, normal kinase activity, and corrected radiosensitivity when expressed in A-T cells indicating neutrality. At least three publications (Mitui_Hum Mut_2009, Magliozzi_DiseaseMarkers_2006, Maxwell_AJHG_2016) and several clinical diagnostic laboratories classify this variant as Benign/Likely Benign. Considering all evidence, the variant was classified as Likely Benign until more information becomes available.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000122822 SCV000745122 likely benign Ataxia-telangiectasia syndrome 2017-05-31 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000588398 SCV000805504 likely benign not provided 2016-03-17 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000588398 SCV000840921 benign not provided 2019-03-13 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000588398 SCV000892001 likely benign not provided 2021-04-01 criteria provided, single submitter clinical testing
Mendelics RCV000122822 SCV001138465 likely benign Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000122822 SCV001266059 likely benign Ataxia-telangiectasia syndrome 2017-04-27 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Baylor Genetics RCV000122822 SCV001481416 uncertain significance Ataxia-telangiectasia syndrome 2020-09-18 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Nilou-Genome Lab RCV000122822 SCV001716380 likely benign Ataxia-telangiectasia syndrome 2021-05-18 criteria provided, single submitter clinical testing
ITMI RCV000120118 SCV000084255 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000115146 SCV000787847 likely benign Hereditary cancer-predisposing syndrome 2018-02-20 no assertion criteria provided clinical testing
Center of Medical Genetics and Primary Health Care RCV001269378 SCV001448733 benign Malignant tumor of breast no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001269378 SCV001551584 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Phe582Leu variant was identified in 3 of 3466 proband chromosomes (frequency: 0.0009) from individuals or families tested for Lynch Syndrome and with breast cancer (Johnson_2007, Yurgelun_2015). The variant was also identified in the following databases: dbSNP (ID: rs2235006) as “With Likely benign allele”, ClinVar (reported 7x, as benign by Invitae, Ambry Genetics, as likely benign by EGL Genetics, PreventionGenetics, University of Chicago, GeneDx, and ITMI without any pathogenicity predictions), Clinvitae (4x, as benign and likely benign by ClinVar, Invitae, EmvClass) and LOVD 3.0 (2x as "Probably does not affect function" prediction). The variant was not identified in the Cosmic or MutDB databases. The variant was identified in control databases in 257 of 276854 chromosomes (1 homozygous) at a frequency of 0.0009 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24020 chromosomes (freq: 0.000042), Other in 11 of 6454 chromosomes (freq: 0.002), Latino in 46 of 34400 chromosomes (freq: 0.0013), European Non-Finnish in 132 of 126444 chromosomes (freq: 0.001), Ashkenazi Jewish in 11 of 10148 chromosomes (freq: 0.001), and South Asian in 56 of 30774 chromosomes (freq: 0.002); it was not in the East Asian, or European Finnish populations. Constructs of the ATM c.1744T>C variant were utilized as a control in an A-T cells transfection study (Mitui_2009). The aim of the experiment was to identify site-directed mutagenesis for distinguishing polymorphisms from mutations in the ATM gene. The study demonstrated that transfecting A-T cells (AT7LA) with constructs of ATM, c.1744T>C variant yielded normal ATM protein levels, normal kinase activity, and corrected radiosensitivity, supporting classification of this variant as likely benign. The p.Phe582 residue is conserved 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. 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000588398 SCV001799379 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000588398 SCV001924842 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000588398 SCV001926952 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000588398 SCV001953808 likely benign not provided no assertion criteria provided clinical testing

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