ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8549T>A (p.Leu2850Ter) (rs876658716)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215215 SCV000274337 pathogenic Hereditary cancer-predisposing syndrome 2019-03-14 criteria provided, single submitter clinical testing The p.L2850* pathogenic mutation (also known as c.8549T>A), located in coding exon 57 of the ATM gene, results from a T to A substitution at nucleotide position 8549. This changes the amino acid from a leucine to a stop codon within coding exon 57. 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.
GeneDx RCV000519674 SCV000617954 pathogenic not provided 2020-03-05 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 at a significant frequency in large population cohorts (Lek 2016); Observed in an individual with colon polyps (Rosenthal 2018); This variant is associated with the following publications: (PMID: 30267214)
Invitae RCV000526852 SCV000622827 pathogenic Ataxia-telangiectasia syndrome 2020-09-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu2850*) 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 observed in individual(s) with Colorectal cancer and adenomatous polyps (PMID: 30267214). ClinVar contains an entry for this variant (Variation ID: 230697). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000215215 SCV000682495 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000526852 SCV000916549 likely pathogenic Ataxia-telangiectasia syndrome 2018-02-09 criteria provided, single submitter clinical testing Variant summary: ATM c.8549T>A (p.Leu2850X) 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. A truncation downstream of this position, c.8977C>T (p.Arg2993X) have been classified as pathogenic by our laboratory. To our knowledge, no occurrence of c.8549T>A in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Multiple clinical diagnostic laboratories via ClinVar (evaluation after 2014) classified the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000526852 SCV001338763 pathogenic Ataxia-telangiectasia syndrome criteria provided, single submitter clinical testing In addition, the heterozygous nonsense variant c.8549T>A; p.Leu2850Ter was detected in exon 58 in the ATM gene, which was derived from the patient's father. The variant replaces the codon for the amino acid leucine (TTG) with a premature stop codon (TAG). In the population-related database gnomAD it is once recorded in heterozygous form among the European population (allele frequency: 0.0003982%), in the other population-related databases it is not listed. In the phenotype-related database HGMD it is once identified as possibly pathogenic, in ClinVar it is assessed four times as pathogenic and once as likely pathogenic, in LOVD it is not listed. The ACMG classification for this variant is: pathogenic (Class 5: PVS1, PM2, PM3, PP5).
CeGaT Praxis fuer Humangenetik Tuebingen RCV000519674 SCV001371328 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing

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