Submissions for variant NM_000051.4(ATM):c.2127T>C (p.Ile709=)

gnomAD frequency: 0.00102  dbSNP: rs56252953

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122831	SCV000166088	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000211973	SCV000167070	benign	not specified	2013-12-31	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	RCV000123727	SCV000213052	likely benign	Hereditary cancer-predisposing syndrome	2014-07-03	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	RCV000122831	SCV000367032	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000123727	SCV000682029	benign	Hereditary cancer-predisposing syndrome	2015-04-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211973	SCV000918556	benign	not specified	2018-08-03	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2127T>C (p.Ile709Ile) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0013 in 275790 control chromosomes, predominantly at a frequency of 0.019 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 18.99 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.2127T>C in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory, University of Chicago	RCV000211973	SCV002070661	benign	not specified	2019-05-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000211973	SCV002774010	benign	not specified	2020-10-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149831	SCV003837831	benign	Breast and/or ovarian cancer	2022-03-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589596	SCV005083863	benign	Familial cancer of breast	2024-05-07	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.
True Health Diagnostics	RCV000123727	SCV000787850	likely benign	Hereditary cancer-predisposing syndrome	2017-10-26	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000122831	SCV001461089	likely benign	Ataxia-telangiectasia syndrome	2020-01-13	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000211973	SCV001552750	benign	not specified		no assertion criteria provided	clinical testing	The ATM p.Ile709= variant was identified in 2 of 200 proband chromosomes (frequency: 0.01) from individuals or families with Hodgkin Disease from Canadian and Japanese pediatric patients, and was not identified in 200 control chromosomes from healthy individuals (Sipahimalani 2007, Takagi 2017). The variant was also identified in dbSNP (ID: rs56252953) as “with uncertain significance, other allele”; in ClinVar and Clinvitae databases as benign by Invitae, GeneDx, as likely benign by Ambry Genetics and as uncertain significance by Illumina Clinical Services. In addition, the variant was identified in the 1000 Genomes Project in 8 of 5000 chromosomes (frequency: 0.002). The variant was identified in control databases in 354 (1 homozygous) of 275790 chromosomes at a frequency of 0.001 in the following populations: East Asian in 351of 18624 chromosomes (freq. 0.02), South Asian in 1 of 30600 chromosomes (freq. 0.00003), other in 2 of 6418 chromosomes (freq. 0.0003), but was not seen in African, Latino, European Non-Finnish, Ashkenazi Jewish, and European Finnish populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The variant was not identified in Cosmic, MutDB, LOVD 3.0, ATM-LOVD, databases or in the NHLBI GO Exome Sequencing Project. The p.Ile709Ile 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 addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.