ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1986T>C (p.Phe662=) (rs1800055)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122829 SCV000166086 benign Ataxia-telangiectasia syndrome 2020-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000211971 SCV000167067 benign not specified 2014-01-17 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 RCV000123724 SCV000213136 likely benign Hereditary cancer-predisposing syndrome 2014-08-07 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.
Color Health, Inc RCV000123724 SCV000537413 likely benign Hereditary cancer-predisposing syndrome 2015-08-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282288 SCV000602570 likely benign none provided 2019-12-23 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000123724 SCV000679688 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000211971 SCV000694206 benign not specified 2019-02-14 criteria provided, single submitter clinical testing Variant summary: ATM c.1986T>C alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00048 in 277242 control chromosomes, predominantly at a frequency of 0.0011 within the Ashkenazi Jewish subpopulation and at a frequency of 0.00083 in the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish and Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism. c.1986T>C has been reported in the literature in individuals affected with cancer, including breast cancer, non-Hodgkin lymphoma and chronic lymphocytic leukemia (Skowronska_2012, Bernstein_2010, Sipahimalani_2007, Vorechovsky_1996). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported in our internal database (PALB2 c.761C>G, p.Ser254X; BRCA1 c.68_69delAG, p.E23fs*17), providing supporting evidence for a benign role. Additionally, the variant was detected in heterozygous state in 12 control individuals in the FLOSSIES database (individuals aged over 70 who never had cancer), providing further supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Counsyl RCV000122829 SCV000788483 likely benign Ataxia-telangiectasia syndrome 2018-03-29 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000586136 SCV001143098 benign not provided 2018-11-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586136 SCV001148406 likely benign not provided 2020-09-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000122829 SCV001266061 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.
True Health Diagnostics RCV000123724 SCV000787848 likely benign Hereditary cancer-predisposing syndrome 2017-11-09 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356414 SCV001551576 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Phe662= variant was identified in 2 of 348 proband chromosomes (frequency: 0.006) from Swedish and Canadian individuals or families with breast cancer (and a family history of tumours associated with AT) and non-Hodgkin lymphoma, and was not identified in 126 control chromosomes from healthy individuals (Vorechovsky_1996_ 8797579, Sipahimalani_2007_17640065). The variant was also found in 2 cell lines derived from non-lymphoid malignancies (Ejima_2000_ 10738255). The variant was identified in dbSNP (ID: rs1800055) “With Likely benign allele”, ClinVar (classified benign by GeneDx, and likely benign by Invitae, Ambry Genetics, Color Genomics Inc and ARUP), Clinvitae (3x), and was not identified in Cosmic, MutDB, LOVD 3.0, or ATM-LOVD. The variant was also identified in control databases in 133 of 277116 chromosomes at a frequency of 0.0005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observation by population include: African in 2 of 24036 chromosomes (freq: 0.00008), “Other” in 3 of 6460 chromosomes (freq: 0.0005), Latino in 10 of 34418 chromosomes (freq: 0.0003), European Non-Finnish in 105 of 126626 chromosomes (freq: 0.0008), Ashkenazi Jewish in 11 of 10148 chromosomes (freq: 0.001), and European Finnish in 2 of 25782 chromosomes (freq: 0.00008); it was not observed in the East Asian and South Asian populations. The p.Phe662= 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000586136 SCV001807596 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000586136 SCV001905830 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000586136 SCV001958964 likely benign not provided no assertion criteria provided clinical testing

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