Submissions for variant NM_000051.4(ATM):c.1541G>A (p.Gly514Asp)

gnomAD frequency: 0.01889  dbSNP: rs2235000

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120115	SCV000167064	benign	not specified	2013-10-29	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	RCV000128890	SCV000172750	benign	Hereditary cancer-predisposing syndrome	2014-10-24	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.
Vantari Genetics	RCV000128890	SCV000266235	benign	Hereditary cancer-predisposing syndrome	2016-02-04	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224639	SCV000281397	benign	not provided	2016-04-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120115	SCV000301653	benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120115	SCV000341036	benign	not specified	2016-05-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000401591	SCV000367029	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.
Invitae	RCV000401591	SCV000558304	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128890	SCV000681980	benign	Hereditary cancer-predisposing syndrome	2014-11-21	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000224639	SCV000840918	benign	not provided	2017-09-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224639	SCV000883427	benign	not provided	2023-11-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000401591	SCV001138464	benign	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225355	SCV002505128	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128890	SCV002532716	benign	Hereditary cancer-predisposing syndrome	2020-02-24	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149817	SCV003837826	benign	Breast and/or ovarian cancer	2021-12-07	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315721	SCV004016409	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120115	SCV004027152	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
ITMI	RCV000120115	SCV000084252	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000128890	SCV000787845	benign	Hereditary cancer-predisposing syndrome	2017-11-14	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000401591	SCV001461006	benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357424	SCV001552893	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Gly514Asp variant was identified in 4 of 4396 proband chromosomes (frequency: 0.0009) from individuals or families with hereditary breast and ovarian cancer and was present in 6 of 2399 control chromosomes (frequency: 0.0025) from healthy individuals (Tavtigian 2009, Teraoka 2001, Thorstenson 2001). The variant was also identified in dbSNP (ID: rs2235000) as “with other allele”. The variant was not identified in ClinVar, Clinvitae, Cosmic, MutDB, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 1603 of 277074 chromosomes (41 homozygous) at a frequency of 0.005785 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1456 (41 homozygous) of 24022 chromosomes (freq: 0.06061), Other in 20 of 6458 chromosomes (freq: 0.003097), Latino in 101 of 34412 chromosomes (freq: 0.002935), European (Non-Finnish) in 18 of 126604 chromosomes (freq: 0.000142), and SouthA sian in 8 of 30780 chromosomes (freq: 0.00026). while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) populations. The p.Gly514Asp 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	RCV000120115	SCV001905694	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000224639	SCV001932769	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120115	SCV001951044	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000224639	SCV002036568	likely benign	not provided		no assertion criteria provided	clinical testing