Submissions for variant NM_000051.4(ATM):c.7494T>C (p.Ser2498=)

gnomAD frequency: 0.00010  dbSNP: rs34393781

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212070	SCV000209576	benign	not specified	2014-07-16	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	RCV000159594	SCV000213204	likely benign	Hereditary cancer-predisposing syndrome	2014-07-16	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205045	SCV000260316	likely benign	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159594	SCV000537460	likely benign	Hereditary cancer-predisposing syndrome	2015-07-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212070	SCV000694354	likely benign	not specified	2019-06-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000205045	SCV000788910	likely benign	Ataxia-telangiectasia syndrome	2016-12-23	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000589020	SCV000840961	uncertain significance	not provided	2018-04-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212070	SCV002070768	likely benign	not specified	2019-10-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000159594	SCV002538026	likely benign	Hereditary cancer-predisposing syndrome	2020-10-28	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589020	SCV004222162	uncertain significance	not provided	2018-04-26	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00018 (9/50684 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on ATM mRNA splicing yielded inconclusive findings. Based on the available information, we are unable to determine the clinical significance of this variant.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492636	SCV004239472	likely benign	Breast and/or ovarian cancer	2023-03-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551364	SCV004740385	likely benign	ATM-related disorder	2019-05-23	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Myriad Genetics, Inc.	RCV004589650	SCV005083931	benign	Familial cancer of breast	2024-06-14	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.
Natera, Inc.	RCV000205045	SCV001452135	likely benign	Ataxia-telangiectasia syndrome	2020-04-18	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356383	SCV001551535	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The ATM p.Ser2498= variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (rs34393781) as “with uncertain significance allele”, ClinVar (interpreted as "likely benign" by Invitae and 3 others, "uncertain significance" by Integrated Genetics and "benign" by GeneDx). The variant was identified in control databases in 17 of 276,992 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24,032 chromosomes (freq: 0.00008), European in 15 of 126,500 chromosomes (freq: 0.0001), but not in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The p.Ser2498= 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 nucleotide is not highly conserved among mammals 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 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.