ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7928-10T>C (rs188404773)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588523 SCV000149167 uncertain significance not provided 2018-10-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.7928-10T>C or IVS53-10T>C and consists of a T>C nucleotide substitution at the -10 position of intron 53 of the ATM gene. In silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. This variant has been reported in one individual with breast cancer (Decker 2017). ATM c.7928-10T>C was observed at an allele frequency of 0.23% (56/24,028) in individuals of African ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether ATM c.7928-10T>C is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001083708 SCV000252601 benign Ataxia-telangiectasia syndrome 2020-11-25 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000115258 SCV000593491 uncertain significance not specified 2015-09-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588523 SCV000694365 uncertain significance not provided 2017-02-16 criteria provided, single submitter clinical testing Variant summary: The ATM c.7928-10T>C variant involves the alteration of a conserved intronic nucleotide and 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 23/121240 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.002033 (21/10330). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Clinical diagnostic laboratories have classified this variant with conflicting classifications as uncertain significance (1) as well as benign (1). Therefore, this variant has been classified as a "Variant of Uncertain Significance - Possibly Benign."
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000115258 SCV000861178 likely benign not specified 2018-05-29 criteria provided, single submitter clinical testing
Color Health, Inc RCV000776053 SCV000910677 likely benign Hereditary cancer-predisposing syndrome 2015-09-22 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000588523 SCV001143121 benign not provided 2019-05-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357331 SCV001552773 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM c.7928-10T>C variant was not identified in the literature. The variant was identified in dbSNP (ID: rs188404773) as "With Uncertain significance allele", ClinVar (classified as benign by Invitae, as likely benign by EGL Genetic Diagnostics, and as uncertain significance by GeneDx, University of Chicago and Integrated Genetics), and in LOVD 3.0 (classified as likely benign by VKGL data sharing initiative).The variant was identified in control databases in 60 of 276948 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 6460 chromosomes (freq: 0.00016), Latino in 2 of 34418 chromosomes (freq: 0.00006), European Non-Finnish in 1 of 126484 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The ATM c.7928-10T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 0 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% 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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