ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.2572T>C (p.Phe858Leu)

gnomAD frequency: 0.00861  dbSNP: rs1800056
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Total submissions: 31
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000119188 SCV000153925 benign Ataxia-telangiectasia syndrome 2025-02-04 criteria provided, single submitter clinical testing
GeneDx RCV000120127 SCV000167073 benign not specified 2013-09-11 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 RCV000131019 SCV000185946 benign Hereditary cancer-predisposing syndrome 2014-07-14 criteria provided, single submitter clinical testing This alteration is classified as 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.
Eurofins Ntd Llc (ga) RCV000120127 SCV000226547 benign not specified 2015-02-09 criteria provided, single submitter clinical testing
Vantari Genetics RCV000131019 SCV000266990 benign Hereditary cancer-predisposing syndrome 2015-10-13 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131019 SCV000292110 benign Hereditary cancer-predisposing syndrome 2014-11-21 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV000120127 SCV000301657 benign not specified criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000415872 SCV000493585 benign not provided 2024-11-01 criteria provided, single submitter clinical testing ATM: BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000415872 SCV000602562 benign not provided 2023-10-26 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000131019 SCV000679692 likely benign Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000415872 SCV000694229 benign not provided 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The ATM c.2572T>C variant affects a conserved nucleotide, resulting in an amino acid change from Phe to Leu. 4/4 in-silico tools predict benign outcome for this variant (SNPs&GO not captured due to low reliability index), and a functional test based on p21 gene induction after parallel treatment of leukemic cells with fludarabine and doxorubicinfunctional support a benign outcome (Navrkalova_Haematologica_2013). This variant was found in 1165/126138 control chromosomes (16 homozygotes) at a frequency of 0.0092359, which is about 2 times of the maximal expected frequency of an ATM pathogenic allele (0.0039528), suggesting this variant is benign. The variant was included in several risk association studies, 5/6 of which found no significanct association between the variant and breast cancer, however one association study found a statistically significant association with the F858L polymorphism and chronic lymphocytic leukemia risk, both alone and in combination with the second ATM polymorphism P1054R, which are in strong linkage disequilibrium (Rudd_2006). In addition, clinical laboratories classified this variant as benign. Taken together, this variant was classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000119188 SCV000743724 likely benign Ataxia-telangiectasia syndrome 2014-10-09 criteria provided, single submitter clinical testing
Counsyl RCV000119188 SCV000790511 likely benign Ataxia-telangiectasia syndrome 2017-03-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000119188 SCV001262552 likely benign 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genome-Nilou Lab RCV000119188 SCV001712299 benign Ataxia-telangiectasia syndrome 2021-05-18 criteria provided, single submitter clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino RCV001568359 SCV001786705 benign Tip-toe gait 2021-05-31 criteria provided, single submitter clinical testing We examined a family. The child is toe-walker and has Phe858Leu variant. Father is not toe-walker and he has this variant too. This variant probably has no clinical relevance, as it occurs frequently, and no disease relevance is predicted for the amino acid change from phenylalanine to leucine according to the calculation of various in-silico prediction programs (Polyphen2, SIFT, Mutation Taster). In the ClinVar mutation database there are also mostly entries "benign" and "likely benign" vs.VUS. Gait disorder
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798374 SCV002041991 benign Breast and/or ovarian cancer 2019-05-24 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV002225352 SCV002505327 benign Hereditary breast ovarian cancer syndrome 2022-04-19 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000120127 SCV002549987 benign not specified 2023-08-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120127 SCV002773996 benign not specified 2021-07-19 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV004589585 SCV005083905 benign Familial cancer of breast 2024-05-09 criteria provided, single submitter clinical testing This variant is considered 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]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Breakthrough Genomics, Breakthrough Genomics RCV000415872 SCV005215837 likely benign not provided criteria provided, single submitter not provided
ITMI RCV000120127 SCV000084265 not provided not specified 2013-09-19 no assertion provided reference population
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000119188 SCV000745810 benign Ataxia-telangiectasia syndrome 2015-05-04 no assertion criteria provided clinical testing
True Health Diagnostics RCV000131019 SCV000787854 benign Hereditary cancer-predisposing syndrome 2018-08-03 no assertion criteria provided clinical testing
Natera, Inc. RCV000119188 SCV001462078 benign Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357283 SCV001552704 likely benign Carcinoma of colon no assertion criteria provided clinical testing The ATM p.Phe858Leu variant was identified in 190 of 15454 proband chromosomes (frequency: 0.01) from individuals or families with breast, colon cancer and chronic lymphocytic leukemia, and was present in 672 of 18488 control chromosomes (frequency: 0.036) from healthy individuals (Johnson 2007, Petereit 2013, Renwick 2006, Rudd 2017, Stredrick 2006, Tapia 2008, Webb 2006). The variant was also identified in the following databases dbSNP (ID: rs1800056) as “With Uncertain significance allele ”, ClinVar (classified as benign by GeneDx, Ambry Genetics, Emory Genetics, Vantari Genetics, Color Genomics, Prevention Genetics, Invitae; classified as uncertain significance by Praxis), Clinvitae (classified as benign by ClinVar), Cosmic, MutDB (classified as polymorphism), LOVD 3.0 (not classified), ATM-LOVD (unknown). ATM-LOVD also reports that there are known homozygous individuals who are unaffected. The variant was identified in control databases in 2373 of 277178 chromosomes (22 homozygous) at a frequency of 0.009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 1805 of 126686 chromosomes (freq: 0.014), Ashkenazi Jewish in 135 of 10150 chromosomes (freq: 0.013), Other in 70 of 6466 chromosomes (freq: 0.011). The p.Phe858 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. There is conflicting information in the literature about the association of the p.Phe858Leu variant with an increased risk of cancer. The study by Fletcher (2010) suggests the variant associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. The study by Stredrick (2006) suggests the variant is associated with a significant increased risk for breast cancer in the U.S. Heterozygote frequencies for p.Phe858Leu were slightly higher in subjects with a first degree relative with breast cancer compared to those with a negative family history. The variant was found in strong linkage disequilibrium associated with increased risk of chronic lymphocytic leukemia (Rudd 2017). Cell lines from breast cancer patients harboring the linked heterozygous p.Phe858Leu variants exhibited increased radiosensitivity (Gutiérrez-Enríquez 2004). The variant is also showing a significant association with risk of colon cancer and predicted to be deleterious by Webb (2006). The minor alleles of ATM p.Phe858Leu were significantly over-represented in cases, compared with controls. At the same time Tapia (2008) suggests this variant is not associated with breast cancer in his group of study showing higher frequencies in the control group than in cases. 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 RCV000120127 SCV001905878 benign not specified no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000120127 SCV001918676 benign not specified no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000120127 SCV001951752 benign not specified no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000120127 SCV002035542 benign not specified no assertion criteria provided clinical testing

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