Total submissions: 31
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000119188 | SCV000153925 | benign | Ataxia-telangiectasia syndrome | 2025-02-04 | criteria provided, single submitter | clinical testing | |
Gene |
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 |
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, |
RCV000131019 | SCV000292110 | benign | Hereditary cancer-predisposing syndrome | 2014-11-21 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV000120127 | SCV000301657 | benign | not specified | criteria provided, single submitter | clinical testing | ||
Ce |
RCV000415872 | SCV000493585 | benign | not provided | 2024-11-01 | criteria provided, single submitter | clinical testing | ATM: BS1, BS2 |
ARUP Laboratories, |
RCV000415872 | SCV000602562 | benign | not provided | 2023-10-26 | criteria provided, single submitter | clinical testing | |
Institute for Biomarker Research, |
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, |
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, |
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, |
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- |
RCV000119188 | SCV001712299 | benign | Ataxia-telangiectasia syndrome | 2021-05-18 | criteria provided, single submitter | clinical testing | |
Practice for Gait Abnormalities, |
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, |
RCV001798374 | SCV002041991 | benign | Breast and/or ovarian cancer | 2019-05-24 | criteria provided, single submitter | clinical testing | |
National Health Laboratory Service, |
RCV002225352 | SCV002505327 | benign | Hereditary breast ovarian cancer syndrome | 2022-04-19 | criteria provided, single submitter | clinical testing | |
Center for Genomic Medicine, |
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, |
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, |
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, |
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, |
RCV000119188 | SCV001462078 | benign | Ataxia-telangiectasia syndrome | 2020-09-16 | no assertion criteria provided | clinical testing | |
Department of Pathology and Laboratory Medicine, |
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, |
RCV000120127 | SCV001905878 | benign | not specified | no assertion criteria provided | clinical testing | ||
Clinical Genetics, |
RCV000120127 | SCV001918676 | benign | not specified | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000120127 | SCV001951752 | benign | not specified | no assertion criteria provided | clinical testing | ||
Laboratory of Diagnostic Genome Analysis, |
RCV000120127 | SCV002035542 | benign | not specified | no assertion criteria provided | clinical testing |