Submissions for variant NM_000051.4(ATM):c.544G>C (p.Val182Leu)

gnomAD frequency: 0.00757  dbSNP: rs3218707

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119106	SCV000153817	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000120166	SCV000167061	benign	not specified	2013-10-25	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	RCV000131001	SCV000185925	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)	RCV000120166	SCV000231466	benign	not specified	2015-03-30	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000131001	SCV000266237	likely 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	RCV000223988	SCV000280714	benign	not provided	2014-09-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131001	SCV000682266	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120166	SCV000805580	benign	not specified	2017-02-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000119106	SCV001260305	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000223988	SCV001477885	benign	not provided	2023-08-11	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000119106	SCV001984724	benign	Ataxia-telangiectasia syndrome	2020-03-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000223988	SCV002047259	benign	not provided	2021-03-30	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225343	SCV002505003	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000120166	SCV002518013	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131001	SCV002528475	benign	Hereditary cancer-predisposing syndrome	2020-09-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120166	SCV002760507	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000223988	SCV003916778	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	ATM: BP4, BS1, BS2
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315697	SCV004016586	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315697	SCV005083950	benign	Familial cancer of breast	2024-04-19	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Breakthrough Genomics, Breakthrough Genomics	RCV000223988	SCV005213516	likely benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000120166	SCV000084308	not provided	not specified	2013-09-19	no assertion provided	reference population
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000119106	SCV000745803	benign	Ataxia-telangiectasia syndrome	2017-09-27	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000131001	SCV000886664	likely benign	Hereditary cancer-predisposing syndrome	2018-11-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354360	SCV001548957	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	ATM, EXON6, c.544G>C, p.Val182Leu, Heterozygous, Benign The ATM p.Val182Leu variant was identified in 7 of 856 proband chromosomes (frequency: 0.008) from a multiethnic American cohort of individuals or families with breast cancer and in 4 of 852 control chromosomes (frequency: 0.005) from healthy women (Bretsky 2003). The variant was also identified in dbSNP (ID: rs3218707) as “With other allele” and ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, Prevention Genetics, and four other submitters; and as likely benign by Vantari Genetics and True Health Diagnostics). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 814 of 273878 chromosomes at a frequency of 0.003 (Genome Aggregation Database Feb 27, 2017), increasing the likelihood this could be a low frequency benign variant. It was observed in the following populations: African in 526 of 23792 chromosomes (freq: 0.02) (1 homozygote in ExAC), Other in 19 of 6360 chromosomes (freq: 0.003), Latino in 159 of 34126 chromosomes (freq: 0.005), European Non-Finnish in 96 of 124726 chromosomes (freq: 0.0008) (1 homozygote in ExAC), Ashkenazi Jewish in 5 of 10042 chromosomes (freq: 0.0005), European Finnish in 7 of 25552 chromosomes (freq: 0.0003), and South Asian in 2 of 30596 chromosomes (freq: 0.00007); it was not observed in the East Asian population. The variant was identified by our laboratory in 6 individuals with breast, colon or endometrial cancers, co-occurring with multiple pathogenic variants: BRCA2, c.2957_2958insG (p.Asn986Lysfs*2) and CHEK2, c.1100del (p.Thr367Metfs*15). The p.Val182 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Leu variant impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. Assessment Date: 2019/07/03 References (PMIDs): 11821961, 12917204, 17640065
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120166	SCV001906397	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000120166	SCV001922882	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120166	SCV001951760	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000223988	SCV002036363	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000119106	SCV002094074	likely benign	Ataxia-telangiectasia syndrome	2019-10-22	no assertion criteria provided	clinical testing