Submissions for variant NM_000051.3(ATM):c.4258C>T (p.Leu1420Phe) (rs1800058)

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000119139	SCV000153854	benign	Ataxia-telangiectasia syndrome	2020-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000116425	SCV000167089	benign	not specified	2013-10-15	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.
Ambry Genetics	RCV000130979	SCV000185896	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-12	criteria provided, single submitter	clinical testing	See homoz.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia	RCV000116425	SCV000257605	benign	not specified	2015-07-15	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000130979	SCV000266991	benign	Hereditary cancer-predisposing syndrome	2016-02-03	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000116425	SCV000301668	benign	not specified		criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000116425	SCV000332306	benign	not specified	2015-06-16	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000130979	SCV000537361	benign	Hereditary cancer-predisposing syndrome	2014-11-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001282437	SCV000602559	benign	none provided	2020-04-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000119139	SCV000743727	likely benign	Ataxia-telangiectasia syndrome	2014-10-09	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000119139	SCV000745813	benign	Ataxia-telangiectasia syndrome	2015-10-05	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130979	SCV000803143	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000119139	SCV001263901	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ITMI	RCV000116425	SCV000084277	not provided	not specified	2013-09-19	no assertion provided	reference population
Genetic Services Laboratory, University of Chicago	RCV000116425	SCV000150350	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.
True Health Diagnostics	RCV000130979	SCV000787864	benign	Hereditary cancer-predisposing syndrome	2018-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001357258	SCV001552677	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Leu1420Phe variant was identified in 81 of 4298 proband chromosomes (frequency: 0.02) from English, French, Dutch, American Indian/Non-Indian, Australian and North American individuals or families with familial and primary breast cancers, AT disease, CML, and individuals undergoing radiation therapy and was present in 108 of 6302 control chromosomes (frequency: 0.02) from healthy individuals (Johnson 2007 , LaPaglia 2010, Broeks 2008, Melo 2001, Petereit 2013, Renwick 2006, Li 2000, Thompson 2005, ). In 2 population-based, case-control studies, the variant was found not to increase breast cancer risk (Einarsdottir 2006, Thompson 2005). The variant was also identified in dbSNP (ID: rs1800058) as “other”, ClinVar (classified as conflicting interpretations of pathogenicity: classified benign by GeneDx, Div of Genomic Diagnostics, Children's Hospital of Philadelphia, Vantari Genetics, Prevention Genetics, Emory Genetics, Color Genomics Inc., Invitae; likely benign by Genetic Services Laboratory, U of Chicago; uncertain significance by Ambry Genetics; and unclassified by ITMI), Clinvitae (5X), LOVD 3.0 (2X), ATM-LOVD (1x). The variant was not identified in GeneInsight-COGR, Cosmic and MutDB. The variant was identified in control databases in 3069 (22 homozygous) of 272226 chromosomes at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 2316 of 124884 chromosomes (freq: 0.019), European (Finnish) in 279 of 25640 chromosomes (freq: 0.011), Other in 67 of 6316 chromosomes (freq: 0.011). The p.Leu1420 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute	RCV000116425	SCV001905884	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics,Academic Medical Center	RCV000116425	SCV001923488	benign	not specified		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000116425	SCV001951036	benign	not specified		no assertion criteria provided	clinical testing