ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1380G>C (p.Thr460=) (rs145333518)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211961 SCV000167063 benign not specified 2014-02-03 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 RCV000123720 SCV000213313 likely benign Hereditary cancer-predisposing syndrome 2014-09-29 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.
Invitae RCV001079887 SCV000252597 benign Ataxia-telangiectasia syndrome 2020-11-25 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000211961 SCV000593477 likely benign not specified 2015-09-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000123720 SCV000681974 likely benign Hereditary cancer-predisposing syndrome 2015-09-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589439 SCV000694182 likely benign not provided 2017-02-16 criteria provided, single submitter clinical testing Variant summary: The ATM c.1380G>C (p.Thr460Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide, which 4/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts alterations to ESE binding. However, these predictions have yet to be confirmed by functional studies. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 23/121350 (1/5277), predominantly in the African cohort, 21/10404 (1/474), which exceeds the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/999 for Breast Cancer. Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of African origin. The variant of interest has not been reported, to our knowledge, in affected individuals via publications. However, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as "likely benign."
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000211961 SCV000861180 likely benign not specified 2018-05-29 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000589439 SCV001143096 benign not provided 2019-05-01 criteria provided, single submitter clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group RCV000123720 SCV001911452 likely benign Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The c.1380G>C p.(Thr460=) variant has an allele frequency of 0.00249 (0.24%, 59/ 23608 alleles) in the African population of the gnomAD v2.1.1 non-cancer dataset (BS1; http://gnomad.broadinstitute.org). It is a silent variant not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike – MaxEntScan – NNSplice - GeneSplicer (BP4). The variant is located at a nucleotide that is not highly conserved across species, based on PhyloP (BP7). Therefore, this variant meets criteria to be classified as likely benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + BP4 + BP7 (PMID: 33280026).
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355437 SCV001550321 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Thr460= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs145333518) as "With Likely benign, other allele", ClinVar (classified as benign by GeneDx and Invitae; as likely benign by Ambry Genetics, University of Chicago, Color Genomics, Integrated Genetics and EGL Genetic Diagnostics), and LOVD 3.0 (classified as likely benign by VKGL data sharing initiative).The variant was identified in control databases in 60 of 277138 chromosomes at a frequency of 0.0002 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 56 of 24028 chromosomes (freq: 0.002), Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 2 of 34402 chromosomes (freq: 0.00006), European Non-Finnish in 1 of 126658 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Thr460= 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 and the nucleotide is not conserved across mammals. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 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.

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