Submissions for variant NM_000051.4(ATM):c.609C>T (p.Asp203=)

gnomAD frequency: 0.00166  dbSNP: rs144709948

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122866	SCV000166124	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000211950	SCV000167062	benign	not specified	2014-01-20	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	RCV000123719	SCV000213018	likely benign	Hereditary cancer-predisposing syndrome	2014-06-27	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.
PreventionGenetics, part of Exact Sciences	RCV000211950	SCV000301679	likely benign	not specified		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000123719	SCV000682306	benign	Hereditary cancer-predisposing syndrome	2016-04-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000122866	SCV000793299	likely benign	Ataxia-telangiectasia syndrome	2017-08-09	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000679133	SCV000840949	benign	not provided	2019-01-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679133	SCV000885038	benign	not provided	2023-09-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000122866	SCV001138438	likely benign	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679133	SCV001148399	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	ATM: BP4, BS1
Illumina Laboratory Services, Illumina	RCV000122866	SCV001262431	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000123719	SCV001911471	likely benign	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.609C>T p.(Asp203=) variant has an allele frequency of 0.00238 (0.23%, 281/ 117988 alleles) in the Non-Finnish European population of the gnomAD v2.1.1 non-cancer dataset (BS1; http://gnomad.broadinstitute.org). It is a silent variant not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created or activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer (BP4). The variant is located at a nucleotide that is not highly conserved across species, based on PhyloP (BP7). Therefore, this variant meets criteria to be classified as likely benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + BP4 + BP7 (PMID: 33280026).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798396	SCV002042706	likely benign	Breast and/or ovarian cancer	2023-04-27	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000211950	SCV002070857	likely benign	not specified	2020-04-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000123719	SCV002537055	likely benign	Hereditary cancer-predisposing syndrome	2021-05-20	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211950	SCV002760508	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679133	SCV002774003	benign	not provided	2023-02-08	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315809	SCV004017269	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000123719	SCV000787876	likely benign	Hereditary cancer-predisposing syndrome	2017-10-30	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000679133	SCV001554085	likely benign	not provided		no assertion criteria provided	clinical testing	The ATM p.Asp203= variant was not identified in the literature nor was it identified in COGR, MutDB, LOVD 3.0, or ATM-LOVD. The variant was identified in dbSNP (ID: rs144709948) as “With other allele”, in ClinVar (4x as likely benign by Ambry Genetics, PreventionGenetics, and the University Midical Center Groningen and 3x as benign by Invitae, GeneDx, and Color Genomics). The variant was also listed the Cosmic database (1x in Acute myeloid leukemia). The variant was identified in control databases in 397 of 276884 chromosomes at a frequency of 0.001 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 12 of 24010 chromosomes (freq: 0.0005), Other in 15 of 6446 chromosomes (freq: 0.002), Latino in 33 of 34358 chromosomes (freq: 0.001), European Non-Finnish in 286 of 126536 chromosomes (freq: 0.002), Ashkenazi Jewish in 5 of 10148 chromosomes (freq: 0.0005), European Finnish in 36 of 25754 chromosomes (freq: 0.001), and South Asian in 10 of 30778 chromosomes (freq: 0.0003) while the variant was not observed in the East Asian, populations. The p.Asp203= 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 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.