Submissions for variant NM_000051.4(ATM):c.4578C>T (p.Pro1526=)

gnomAD frequency: 0.03196  dbSNP: rs1800889

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119133	SCV000153847	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162381	SCV000212691	benign	Hereditary cancer-predisposing syndrome	2014-11-19	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.
PreventionGenetics, part of Exact Sciences	RCV000116426	SCV000301670	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000119133	SCV000367056	benign	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000162381	SCV000537351	benign	Hereditary cancer-predisposing syndrome	2015-03-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000116426	SCV000538366	benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162381	SCV000679693	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000119133	SCV000743728	benign	Ataxia-telangiectasia syndrome	2014-10-10	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000116426	SCV000856495	benign	not specified	2017-08-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705826	SCV001157006	benign	not provided	2023-11-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000119133	SCV001750398	benign	Ataxia-telangiectasia syndrome	2021-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001705826	SCV001895577	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 11505391, 27599564)
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225337	SCV002504718	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162381	SCV002527054	benign	Hereditary cancer-predisposing syndrome	2020-05-22	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000116426	SCV002760571	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315663	SCV004016464	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315663	SCV005084008	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.
Breakthrough Genomics, Breakthrough Genomics	RCV001705826	SCV005216501	likely benign	not provided		criteria provided, single submitter	not provided
Genetic Services Laboratory, University of Chicago	RCV000116426	SCV000150351	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000119133	SCV000732992	benign	Ataxia-telangiectasia syndrome		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162381	SCV000787866	likely benign	Hereditary cancer-predisposing syndrome	2018-03-02	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000119133	SCV001462148	benign	Ataxia-telangiectasia syndrome	2019-08-26	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356512	SCV001551709	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Pro1526= variant was identified in 520 of 9784 proband chromosomes (frequency: 0.05) from individuals or families with unselected multiple myeloma, breast cancer and was identified in 395 of 6700 control chromosomes (frequency: 0.059) from healthy individuals (Austen 2008, Concannon 2008, Petereit 2013, Stredrick 2006, Tommiska 2006). The variant was also identified in dbSNP (ID: rs rs1800889) as “other”, ClinVar (classified as benign by Invitae, Ambry Genetics, Prevention Genetics, Color Genomics; classified as likely benign by Illumina, GSLUOC), Cosmic (classified as neutral), LOVD 3.0 (does not affect function), databases. The variant was not identified in GeneInsight-COGR, MutDB, ATM-LOVD, databases. The variant was identified in control databases in 9064 (227 homozygous) of 277100 chromosomes at a frequency of 0.03 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%: European (Non-Finnish) in 6425 of 126614 chromosomes (freq: 0.051), Other in 212 of 6458 chromosomes (freq: 0.033), Latino in 1062 of 34414 chromosomes (freq: 0.031), European (Finnish) in 641 of 25788 chromosomes (freq: 0.025), Ashkenazi Jewish* in 131 of 10146 chromosomes (freq: 0.013), South Asian in 396 of 30782 chromosomes (freq: 0.013). The p.Pro1526Pro 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. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, few studies suggest the variant not associated with breast cancer risk and classify the variant as SNP (Stredrick 2006, Tommiska 2006). In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000116426	SCV001800467	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000116426	SCV001906001	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000116426	SCV001923647	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000116426	SCV001959229	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000116426	SCV001965831	benign	not specified		no assertion criteria provided	clinical testing