ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.162T>C (p.Tyr54=) (rs3218690)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000119217 SCV000153959 benign Ataxia-telangiectasia syndrome 2020-12-07 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: 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 Praxis fuer Humangenetik Tuebingen RCV000415913 SCV000493479 likely benign not provided 2021-04-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000211941 SCV000593474 likely benign not specified 2017-03-15 criteria provided, single submitter clinical testing
Color Health, Inc 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000119217 SCV000745801 benign Ataxia-telangiectasia syndrome 2017-09-27 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000211941 SCV000805500 benign not specified 2017-08-25 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000415913 SCV000840919 benign not provided 2018-08-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282126 SCV000885034 likely benign none provided 2019-11-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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
Nilou-Genome 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).
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
Human Genetics - Radboudumc,Radboudumc RCV000415913 SCV001951322 likely benign not provided no assertion criteria provided clinical testing

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