ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3049C>T (p.Gln1017Ter) (rs730881388)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211992 SCV000209780 pathogenic not provided 2020-06-10 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 29308099, 26681312, 31447099)
Ambry Genetics RCV000159761 SCV000216002 pathogenic Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing The p.Q1017* pathogenic mutation (also known as c.3049C>T), located in coding exon 19 of the ATM gene, results from a C to T substitution at nucleotide position 3049. This changes the amino acid from a glutamine to a stop codon within coding exon 19. This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 08;18:823-32). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000457084 SCV000546762 pathogenic Ataxia-telangiectasia syndrome 2020-09-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1017*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 181992). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000457084 SCV000694246 pathogenic Ataxia-telangiectasia syndrome 2019-10-28 criteria provided, single submitter clinical testing Variant summary: ATM c.3049C>T (p.Gln1017X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3085dupA (p.Thr1029fsX19), c.3245_3247delinsTGAT (p.His1082fsX14), c.3372C>G (p.Tyr1124X)). The variant was absent in 251048 control chromosomes (gnomAD). c.3049C>T has been reported in the literature in an individual affected with Breast Cancer (Susswein_2016).To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258064 SCV001434895 likely pathogenic Ataxia-telangiectasia syndrome; Breast cancer, susceptibility to 2018-10-08 criteria provided, single submitter clinical testing The c.3049C>T (p.Gln1017*) variant in the ATM gene is predicted to introduce a premature translation termination codon. This variant has not been reported in the gnomAD database. Therefore, the c.3049C>T (p.Gln1017*) variant in the ATM gene is classified as likely pathogenic.

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