ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.8156G>A (p.Arg2719His)

gnomAD frequency: 0.00015  dbSNP: rs55982963
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Total submissions: 26
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586113 SCV000149171 uncertain significance not provided 2024-03-12 criteria provided, single submitter clinical testing Observed in individuals with a personal or family history of breast or other cancers, but also in unaffected controls (PMID: 18384426, 24121791, 25186627, 27153395, 27067391, 28779002, 32522261, 33471991, 35264596); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21445571, 25503501, 18384426, 22529920, 19781682, 24121791, 26580448, 25525159, 27153395, 27067391, 25925381, 30197789, 17344846, 25186627, 28652578, 30287823, 34426522, 35312250, 36029002, 33471991, 35264596, 32522261, 28779002, 15279808, 23532176)
Ambry Genetics RCV000115262 SCV000184388 uncertain significance Hereditary cancer-predisposing syndrome 2024-09-06 criteria provided, single submitter clinical testing The p.R2719H variant (also known as c.8156G>A), located in coding exon 55 of the ATM gene, results from a G to A substitution at nucleotide position 8156. The arginine at codon 2719 is replaced by histidine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals with a personal and/or family history of breast cancer (Brunet J et al. Clin. Genet. 2008 May;73:465-73; Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190; Pereira JZ et al. Mol Biol Rep, 2022 Oct;49:9509-9520; Sánchez Castro EE et al. Rev Fac Cien. Med Univ Nac Cordoba. 2022 03;79(1):53-56.). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000232453 SCV000283074 uncertain significance Ataxia-telangiectasia syndrome 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2719 of the ATM protein (p.Arg2719His). This variant is present in population databases (rs55982963, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with breast cancer (PMID: 18384426, 19781682, 21445571, 35264596). ClinVar contains an entry for this variant (Variation ID: 127456). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health RCV000115262 SCV000682464 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-16 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 2719 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. The variant has been reported in individuals affected with breast cancer (PMID: 18384426, 19781682, 35312250, 33471991, 35312250), as well as in two women older than age 70 years with no personal history of cancer (FLOSSIES; https://whi.color.com/). In a large international case-control meta-analysis, this variant was reported in 22/60466 cases breast cancer cases and 11/53461 controls (OR=1.769, 95%CI 0.858 to 3.648, p-value=0.162; PMID: 33471991). This variant has also been identified in 37/250828 chromosomes in the general population by the Genome Aggregation Database (gnomAD), including 1 homozygous individual. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586113 SCV000694372 uncertain significance not provided 2017-02-16 criteria provided, single submitter clinical testing Variant summary: The c.8156G>A (p.Arg2719His) in ATM gene is a missense change that involves a conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant is located in the PI3/PI4-kinase domain, however no functional studies confirming deleterious effect of this change have been reported at the time of evaluation. The variant is present in the control population dataset of ExAC at a frequency of 0.00017 (20/116502 chrs tested), predominantly in individuals of Latino descent (0.0017; 13/1130chrs tested), including 1 homozygote. The latter frequency exceeds the maximum expected allele frequency for a pathogenic variant of 0.0010, suggesting it is may be an ethnic-specific functional polymorphism. The variant has been reported in BrC pts without strong evidence for causality. The variant is cited as VUS by a reputable databases/clinical laboratories without evidence to independently evaluate. Taking together, the variant was classified as VUS.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000232453 SCV000745134 uncertain significance Ataxia-telangiectasia syndrome 2016-07-27 criteria provided, single submitter clinical testing
Mendelics RCV000232453 SCV000838607 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000764949 SCV000896121 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000586113 SCV001148447 uncertain significance not provided 2024-10-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000232453 SCV001264110 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.
Division of Medical Genetics, University of Washington RCV001257471 SCV001434277 uncertain significance Familial cancer of breast 2019-10-08 criteria provided, single submitter clinical testing This variant has been reported in the literature in individuals with breast cancer (Brunet 2008, Tavtigian 2009, Grana 2011). This variant has an overall allele frequency of 0.0001 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. PP3
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586113 SCV001469960 uncertain significance not provided 2024-02-06 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000586113 SCV001475573 uncertain significance not provided 2020-03-27 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000232453 SCV001781321 uncertain significance Ataxia-telangiectasia syndrome 2021-07-14 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798327 SCV002042975 uncertain significance Breast and/or ovarian cancer 2022-11-22 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001818260 SCV002071379 uncertain significance not specified 2021-02-26 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115262 SCV002527174 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-01 criteria provided, single submitter curation
MGZ Medical Genetics Center RCV001257471 SCV002579417 uncertain significance Familial cancer of breast 2021-09-02 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000232453 SCV003827468 uncertain significance Ataxia-telangiectasia syndrome 2021-09-07 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000586113 SCV004026395 uncertain significance not provided 2023-05-17 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV001257471 SCV005083992 likely benign Familial cancer of breast 2024-06-18 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001818260 SCV005090404 uncertain significance not specified 2024-07-31 criteria provided, single submitter clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund RCV000586113 SCV005199623 uncertain significance not provided 2022-05-27 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000232453 SCV000734791 uncertain significance Ataxia-telangiectasia syndrome no assertion criteria provided clinical testing
Natera, Inc. RCV000232453 SCV001462604 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000586113 SCV001979623 uncertain significance not provided no assertion criteria provided clinical testing

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