Submissions for variant NM_000051.4(ATM):c.4473C>T (p.Phe1491=)

gnomAD frequency: 0.00125  dbSNP: rs4988008

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122850	SCV000166108	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000212018	SCV000167091	benign	not specified	2013-12-24	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	RCV000123748	SCV000212881	likely benign	Hereditary cancer-predisposing syndrome	2016-11-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Illumina Laboratory Services, Illumina	RCV000122850	SCV000367055	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000123748	SCV000682210	benign	Hereditary cancer-predisposing syndrome	2015-04-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587530	SCV000694284	benign	not provided	2016-03-07	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000212018	SCV000701957	benign	not specified	2016-10-24	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000122850	SCV000745126	likely benign	Ataxia-telangiectasia syndrome	2017-06-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000587530	SCV000805566	likely benign	not provided	2017-05-15	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000587530	SCV000840942	benign	not provided	2019-02-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000122850	SCV001138503	likely benign	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587530	SCV001148424	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	ATM: BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798393	SCV002042222	likely benign	Breast and/or ovarian cancer	2023-03-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212018	SCV002070935	likely benign	not specified	2021-09-22	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.4473C>T, in exon 30 which does not result in an amino acid change. This sequence change has been described in the gnomAD database with a frequency of 0.20% in the European sub-population (dbSNP rs4988008). The p.Phe1491Phe change has been identified in a hereditary breast and ovarian cancer family (PMID: 12810666). This sequence change is not predicted to have a deleterious effect on splicing based on in silico splice prediction programs. The p.Phe1491Phe change affects a moderately conserved nucleotide located in a domain of the ATM protein that is not known to be functional. It is likely that this is a normal variant in the ATM gene however functional studies have not been performed to prove this conclusively.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225390	SCV002504717	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000123748	SCV002534834	likely benign	Hereditary cancer-predisposing syndrome	2021-04-13	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212018	SCV002760570	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587530	SCV002773998	benign	not provided	2023-04-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589602	SCV005083996	benign	Familial cancer of breast	2024-05-20	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000122850	SCV000745815	likely benign	Ataxia-telangiectasia syndrome	2017-03-23	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000123748	SCV000886663	likely benign	Hereditary cancer-predisposing syndrome	2018-09-06	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000122850	SCV001462146	likely benign	Ataxia-telangiectasia syndrome	2020-01-05	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354679	SCV001549355	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Phe1491= variant was identified in 1 of 1010 proband chromosomes (frequency: 0.001) from individuals or families with prostate cancer, breast cancer or chronic lymphocytic leukemia, and was present in 6 of 1439 control chromosomes (freq. 0.004) from healthy individuals (Skowronska_2011_21933854, Stock_2013_NA, Rosentein_2006_NA). The variant was also identified in dbSNP (ID: rs4988008) as “With other allele”, Clinvar and Clinvitae (3x classified as benign by Invitae, GeneDx, Color Genomics; 1x classified as likely benign by Ambry Genetics; 1x classified as uncertain significance by Illumina), COSMIC (1x in acute myeloid leukemia, somatic status unconfirmed), and LOVD 3.0 (2 entries, not classified) databases. The variant was not identified in the GeneInsight-COGR or MutDB databases. The variant was identified in control databases in 333 of 277018 chromosomes (0 homozygous) at a frequency of 0.001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 6 of 24020 chromosomes (freq: 0.0002), Other in 9 of 6456 chromosomes (freq: 0.001), Latino in 21 of 34412 chromosomes (freq: 0.0006), European Non-Finnish in 262 of 126558 chromosomes (freq: 0.002), Ashkenazi Jewish in 22 of 10150 chromosomes (freq: 0.002), European Finnish in 13 of 25778 chromosomes (freq: 0.0005) while the variant was not observed in the East Asian and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational predictions software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Phe1491= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000587530	SCV001906187	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000587530	SCV001917746	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000587530	SCV001927759	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587530	SCV001956308	likely benign	not provided		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000123748	SCV001977033	likely benign	Hereditary cancer-predisposing syndrome	2021-09-27	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000587530	SCV002036809	likely benign	not provided		no assertion criteria provided	clinical testing