Submissions for variant NM_000051.4(ATM):c.162T>C (p.Tyr54=)

gnomAD frequency: 0.00200  dbSNP: rs3218690

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119217	SCV000153959	benign	Ataxia-telangiectasia syndrome	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000211941	SCV000167080	benign	not specified	2013-10-23	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	RCV000123737	SCV000213023	likely benign	Hereditary cancer-predisposing syndrome	2014-06-20	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.
CeGaT Center for Human Genetics Tuebingen	RCV000415913	SCV000493479	likely benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	ATM: BP4, BP7
Genetic Services Laboratory, University of Chicago	RCV000211941	SCV000593474	likely benign	not specified	2017-03-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000123737	SCV000681988	benign	Hereditary cancer-predisposing syndrome	2015-04-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000415913	SCV000694189	benign	not provided	2016-01-11	criteria provided, single submitter	clinical testing	Variant summary: This c.162T>C variant affects a non-conserved nucleotide, resulting in synonymous amino acid change. 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. This variant was found in 208/121226 control chromosomes (including the large and broad populations of ExAC) at a frequency of 0.0017158, which does not exceed the maximal expected frequency of a pathogenic allele (0.0039528) in this gene. However, the possibility that this variant can still represents as a rare polymorphism cannot be ruled out from the comparison. The variant is more common in European (Non-Finnish) population where its allele frequency is 0.25% (167/66625 chromosomes) including one homozygous occurrence. The homozygote is suggestive of a benign outcome with respect to early onset recessive phenotype A-T. [Penetrance of variants causing A-T is not exactly known.] This variant has been found in patients with A-T, breast and/or ovarian cancer, chronic lymphocytic leukemia and Hodgkins lymphoma. The publications reporting patient occurrences report this variant as polymorphism. In one A-T patient reported, the patient also carried other two potentially pathogenic variants (Buzin_2003), suggesting a benign outcome for this variant. In addition, this variant was found at similar frequencies in a small case-control study (Liberzon_2004), further supporting a benign outcome. Multiple clinical labs have classified this variant as benign/likely benign. Taken together, this variant has been classified as Benign.
Eurofins Ntd Llc (ga)	RCV000211941	SCV000704532	likely benign	not specified	2016-12-20	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000119217	SCV000745120	likely benign	Ataxia-telangiectasia syndrome	2017-06-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000211941	SCV000805500	benign	not specified	2017-08-25	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000415913	SCV000840919	benign	not provided	2018-08-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000415913	SCV000885034	benign	not provided	2022-09-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000119217	SCV001265965	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262812	SCV001440819	likely benign	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000119217	SCV001652755	likely benign	Ataxia-telangiectasia syndrome	2021-05-18	criteria provided, single submitter	clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000123737	SCV001911485	likely benign	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.162T>C p.(Tyr54=) variant has an allele frequency of 0.00283 (0.23%, 334/ 118012 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/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). This silent variant has been identified in two ataxia telangiectasia patients, but in one case there were also detected two (likely) pathogenic variants (PMID: 12552559) and in the other one, there was also detected an homozygous truncating variant (PMID: 28898322). This, together with the high frequency of the variant in the general population suggests that c.162T>C was just a coincident polymorphism and discards the use of PM3 and PS4 criteria. 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	RCV001798375	SCV002043058	likely benign	Breast and/or ovarian cancer	2022-02-23	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225353	SCV002504936	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000123737	SCV002532782	benign	Hereditary cancer-predisposing syndrome	2020-07-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211941	SCV002760499	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000415913	SCV004220002	benign	not provided	2022-11-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001262812	SCV005083846	benign	Familial cancer of breast	2024-04-17	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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000119217	SCV000745801	benign	Ataxia-telangiectasia syndrome	2017-09-27	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000123737	SCV000787846	likely benign	Hereditary cancer-predisposing syndrome	2018-01-03	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000119217	SCV001461074	likely benign	Ataxia-telangiectasia syndrome	2020-04-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000415913	SCV001554164	likely benign	not provided		no assertion criteria provided	clinical testing	The ATM p.Tyr54= variant was identified in 8 of 1966 proband chromosomes (frequency: 0.004) from Finnish, Dutch and Austrian individuals or families with (BRCA1/2 negative) breast cancer or HBOC, American/non America Indian individuals undergoing radiation therapy, and Jewish children with Hodgkin’s disease (Tommiska_2006_16914028, Thorstenson_2003_12810666, Petereit_2013_24416720, Liberzon_2004_14735203, Broeks_2008_17393301). The variant was identified in dbSNP (ID: rs3218690) “With other allele”, ClinVar (conflicting interpretations of pathogenicity; submitters: benign by Invitae and GeneDx, likely benign by Ambry Genetics and Genetic Services Laboratory (University of Chicago), and uncertain significance by Praxis fur Humangenetik Tuebingen), Clinvitae (4x), and was not identified in GeneInsight-COGR, Cosmic, MutDB, or LOVD 3.0. The variant was also identified in control databases in 486 (1 homozygous) of 276848 chromosomes at a frequency of 0.002 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 14 of 24010 chromosomes (freq: 0.0006), Other in 13 of 6460 chromosomes (freq: 0.002), Latino in 12 of 34408 chromosomes (freq: 0.0003), European Non-Finnish in 359 (1 homozygous) of 126590 chromosomes (freq: 0.003), Ashkenazi Jewish in 24 of 10142 chromosomes (freq: 0.002), European Finnish in 43 of 25762 chromosomes (freq: 0.002), and South Asian in 21 of 30610 chromosomes (freq: 0.0007) while not observed in the East Asian population. The p.Tyr54= 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000211941	SCV001905839	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000211941	SCV001919694	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000415913	SCV001931660	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000415913	SCV001951322	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000415913	SCV002036364	likely benign	not provided		no assertion criteria provided	clinical testing