Submissions for variant NM_000051.4(ATM):c.1744T>C (p.Phe582Leu)

gnomAD frequency: 0.00071  dbSNP: rs2235006

Total submissions: 32

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122822	SCV000166079	benign	Ataxia-telangiectasia syndrome	2024-01-31	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: 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)	RCV000120118	SCV000225147	likely benign	not specified	2015-03-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	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 Diagnostics, LLC DBA Color Health	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
Athena Diagnostics	RCV000588398	SCV000840921	benign	not provided	2019-03-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588398	SCV000892001	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	ATM: BP4
Mendelics	RCV000122822	SCV001138465	likely benign	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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].
Genome-Nilou Lab	RCV000122822	SCV001716380	likely benign	Ataxia-telangiectasia syndrome	2021-05-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798308	SCV002043338	likely benign	Breast and/or ovarian cancer	2023-02-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115146	SCV002533320	likely benign	Hereditary cancer-predisposing syndrome	2021-02-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120118	SCV002760524	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588398	SCV002773994	benign	not provided	2023-09-21	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315634	SCV004016508	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315634	SCV005083855	likely benign	Familial cancer of breast	2024-05-01	criteria provided, single submitter	clinical testing	This variant is considered likely benign. 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].
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588398	SCV001953808	likely benign	not provided		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115146	SCV001977043	benign	Hereditary cancer-predisposing syndrome	2021-09-27	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000120118	SCV001977786	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000122822	SCV002083790	likely benign	Ataxia-telangiectasia syndrome	2019-10-30	no assertion criteria provided	clinical testing