Submissions for variant NM_000051.4(ATM):c.1636C>G (p.Leu546Val)

gnomAD frequency: 0.01541  dbSNP: rs2227924

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120117	SCV000167065	benign	not specified	2013-10-01	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	RCV000128892	SCV000172752	benign	Hereditary cancer-predisposing syndrome	2014-11-25	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)	RCV000120117	SCV000225148	benign	not specified	2015-02-16	criteria provided, single submitter	clinical testing
Invitae	RCV000205062	SCV000262429	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224104	SCV000280796	benign	not provided	2015-12-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120117	SCV000301654	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000205062	SCV000367030	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.
Color Diagnostics, LLC DBA Color Health	RCV000128892	SCV000681989	benign	Hereditary cancer-predisposing syndrome	2014-11-05	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000224104	SCV000840920	benign	not provided	2018-05-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224104	SCV001472243	benign	not provided	2023-08-24	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225356	SCV002505139	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128892	SCV002530987	benign	Hereditary cancer-predisposing syndrome	2020-03-21	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002492416	SCV002802846	likely benign	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-11-10	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149818	SCV003837599	benign	Breast and/or ovarian cancer	2021-07-02	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315722	SCV004016608	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120117	SCV004027154	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224104	SCV004133240	benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	ATM: BP4, BS1, BS2
ITMI	RCV000120117	SCV000084254	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000128892	SCV000805210	benign	Hereditary cancer-predisposing syndrome	2018-06-18	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000205062	SCV001461008	benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120117	SCV001554305	benign	not specified		no assertion criteria provided	clinical testing	The ATM p.Leu546Val variant was identified in 2 of 290 proband chromosomes (frequency: 0.007) from individuals or families with breast cancer or multiple myeloma and was not identified in 400 control chromosomes from healthy individuals (Austen 2008, Mangone 2015). The variant was also identified in the following databases: ClinVar (classified 6x as Benign, 1x as Likely Benign), Clinvitae (classified as 4x Benign, 1x conflicting interpretation of pathogenicity), Cosmic (1x as neutral), ATM-LOVD (1x effect unknown). The variant was not identified in MutDB or LOVD 3.0 databases. The variant was identified in control databases in 1340 of 277018 (35 homozygous) chromosomes at a frequency of 0.005 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 1217 of 24034 chromosomes (freq: 0.051). One group studied the kinase activity of variants of ATM and found the p.Leu546Val variant to maintain normal kinase activity (Austen, 2008). The p.Leu546Val 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 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000120117	SCV001743910	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120117	SCV001906283	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000120117	SCV001923063	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120117	SCV001959445	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000120117	SCV001978127	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120117	SCV002035768	benign	not specified		no assertion criteria provided	clinical testing