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

gnomAD frequency: 0.00861  dbSNP: rs1800056

Total submissions: 31

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	2025-02-01	criteria provided, single submitter	clinical testing	ATM: BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000415872	SCV000602562	benign	not provided	2024-10-23	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	2025-03-04	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