ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.146C>G (rs1800054)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122818 SCV000166075 benign Ataxia-telangiectasia syndrome 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000176968 SCV000167079 benign not specified 2013-10-03 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 RCV000128940 SCV000172814 benign Hereditary cancer-predisposing syndrome 2014-06-19 criteria provided, single submitter clinical testing This alteration is classified as 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000176968 SCV000228761 benign not specified 2015-02-27 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224620 SCV000280894 likely benign not provided 2015-09-28 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
PreventionGenetics,PreventionGenetics RCV000176968 SCV000301652 benign not specified criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224620 SCV000493597 likely benign not provided 2016-06-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000128940 SCV000537372 benign Hereditary cancer-predisposing syndrome 2014-12-08 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000128940 SCV000576455 likely benign Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000176968 SCV000593473 likely benign not specified 2017-06-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282301 SCV000602555 benign none provided 2020-01-20 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000122818 SCV000743718 likely benign Ataxia-telangiectasia syndrome 2014-10-09 criteria provided, single submitter clinical testing
GeneKor MSA RCV000128940 SCV000821790 likely benign Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000176968 SCV000916542 benign not specified 2018-02-16 criteria provided, single submitter clinical testing Variant summary: ATM c.146C>G (p.Ser49Cys) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0072 in 277324 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.013 in the gnomAD database, including 10 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold above the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001). The allele frequency of this variant in a cohort of individuals who are cancer-free and older than 70 years is 0.025 (185/7325), which is even higher than the allele frequency in the general controls (gnomAD Non-Finnish European, 0.013). These data strongly suggest that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The c.146C>G variant has been reported in the literature in individuals affected with Breast Cancer, though one study reported a lack of cosegregation of the variant with disease in two family members of a proband (Allinen_2002). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. A case control study seeking to evaluate whether the variant increases the risk of breast cancer raised the possibility that the variant may be a breast cancer susceptibility allele (Stredrick_2006). However, a much larger cohort from Fletcher_2012 failed to prove the same. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV000122818 SCV001265964 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Practice for Gait Abnormalities, David Pomarino,Competency Network Toe Walking c/o Practice Pomarino RCV001353116 SCV001548277 uncertain significance Toe walking 2020-10-06 criteria provided, single submitter clinical testing
OMIM RCV000003189 SCV000023347 risk factor Breast cancer, susceptibility to 2006-06-01 no assertion criteria provided literature only
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000122818 SCV000745800 benign Ataxia-telangiectasia syndrome 2015-11-20 no assertion criteria provided clinical testing
True Health Diagnostics RCV000128940 SCV000787844 likely benign Hereditary cancer-predisposing syndrome 2018-02-14 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357240 SCV001552651 benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Ser49Cys variant was identified in 84 of 6116 proband chromosomes (frequency: 0.01) from individuals or families with ataxia telangiectasia and breast cancer and was present in 58 of 7048 control chromosomes (frequency: 0.008) from healthy individuals (Castellvi-Bei 1999, Petereit 2013, Schneider 2006, Stedrick 2006). The variant was identified in dbSNP (rs1800054) as “with uncertain significance, other allele”, ClinVar (classified as benign by Color, Ambry Genetics, Invitae and 6 other submitters and likely benign by True Health Diagnostics, University of Chicago and 5 other submitters) and LOVD 3.0 (observed 10x). The variant was identified in control databases in 2005 of 276,924 chromosomes (12 homozygous) at a frequency of 0.007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 65 of 24,012 chromosomes (freq: 0.003), Other in 30 of 6462 chromosomes (freq: 0.005), Latino in 105 of 34,412 chromosomes (freq: 0.003), European in 1615 of 126,588 chromosomes (freq: 0.01), Ashkenazi Jewish in 6 of 10,148 chromosomes (freq: 0.0006), Finnish in 67 of 25,760 chromosomes (freq: 0.003) and South Asian in 117 of 30,674 chromosomes (freq: 0.004). The variant was not observed in the East Asian population. The variant was expressed in vitro and had reduced but detectable levels of ATM (Becker-Catania 2000). The p.Ser49 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

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