ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.544G>C (p.Val182Leu) (rs3218707)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000119106 SCV000153817 benign Ataxia-telangiectasia syndrome 2020-12-02 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: 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 Health, Inc RCV000131001 SCV000682266 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000119106 SCV000745803 benign Ataxia-telangiectasia syndrome 2017-09-27 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120166 SCV000805580 benign not specified 2017-02-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 RCV001289886 SCV001477885 benign none provided 2019-09-04 criteria provided, single submitter clinical testing
ITMI RCV000120166 SCV000084308 not provided not specified 2013-09-19 no assertion provided reference population
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
Human Genetics - Radboudumc,Radboudumc RCV000120166 SCV001951760 benign not specified no assertion criteria provided clinical testing

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