Submissions for variant NM_000051.4(ATM):c.1176C>G (p.Gly392=)

gnomAD frequency: 0.00388  dbSNP: rs1800727

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV002221497	SCV002499275	benign	Familial cancer of breast	2022-03-09	reviewed by expert panel	curation	The ATM c.1176C>G (p.Gly392=) variant has a GnomAD (v2.1.1) filtering allele frequency of 4.878% (AFR) which is above the ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 500031, 61756). This is a synonymous variant (BP7) and in silico predictors find that this variant is unlikely to affect splicing (Splice AI/MaxENTScan 0%) (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.
Ambry Genetics	RCV000130991	SCV000185914	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.
PreventionGenetics, part of Exact Sciences	RCV000247410	SCV000301650	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000386773	SCV000367026	benign	Ataxia-telangiectasia syndrome	2018-01-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000386773	SCV000558356	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130991	SCV000681955	benign	Hereditary cancer-predisposing syndrome	2015-04-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000386773	SCV000797300	benign	Ataxia-telangiectasia syndrome	2018-01-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705930	SCV001477910	benign	not provided	2023-08-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001705930	SCV001833949	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17333338)
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225439	SCV002505072	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149905	SCV003838947	benign	Breast and/or ovarian cancer	2021-07-12	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV002221497	SCV004016025	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000247410	SCV004027146	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002221497	SCV005083830	benign	Familial cancer of breast	2024-04-25	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	RCV001705930	SCV005230999	benign	not provided		criteria provided, single submitter	not provided
True Health Diagnostics	RCV000130991	SCV000787841	likely benign	Hereditary cancer-predisposing syndrome	2018-02-23	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000386773	SCV001456883	benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354336	SCV001548931	benign	Bile duct cancer		no assertion criteria provided	clinical testing	The ATM p.Gly392= variant was identified in dbSNP (ID: rs1800727) as “With other allele”, ClinVar (classified benign by Ambry Genetics, Prevention Genetics and Invitae, and likely benign by Illumina), Clinvitae (3x), Cosmic (2x in a haematopoietic neoplasm), LOVD 3.0, and in control databases in 1348 (34 homozygous) of 276972 chromosomes at a frequency of 0.005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1208 (34 homozygous) of 24022 chromosomes (freq: 0.05), Other in 22 of 6456 chromosomes (freq: 0.003), Latino in 90 of 34396 chromosomes (freq: 0.003), and European in 28 of 126546 chromosomes (freq: 0.0002), while it not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant was not identified in GeneInsight-COGR or the MutDB database. The p.Gly392= 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 this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000247410	SCV001808204	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000247410	SCV001905971	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000247410	SCV001918461	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000247410	SCV002034146	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000247410	SCV002035682	benign	not specified		no assertion criteria provided	clinical testing