ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.7913G>A (p.Trp2638Ter) (rs377349459)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129649 SCV000184447 pathogenic Hereditary cancer-predisposing syndrome 2018-06-01 criteria provided, single submitter clinical testing The p.W2638* pathogenic mutation (also known as c.7913G>A), located in coding exon 52 of the ATM gene, results from a G to A substitution at nucleotide position 7913. This changes the amino acid from a tryptophan to a stop codon within coding exon 52. This mutation has been reported in a compound heterozygous or homozygous state in multiple individuals with classic ataxia-telangiectasia (Sasaki T et al. Hum. Mutat. 1998;12:186-95; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Coutinho G et al. Am. J. Med. Genet. A. 2004 Apr;126A:33-40​; Demuth I et al. Neurogenetics. 2011 Nov;12:273-82). This mutation was also detected in 1/692 men with metastatic prostate cancer (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). 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.
GeneDx RCV000212077 SCV000209648 pathogenic not provided 2020-12-11 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; Observed in the heterozygous state in individuals with ATM-related cancers (Pritchard 2016, Adedokun 2020); This variant is associated with the following publications: (PMID: 25525159, 23774824, 9711876, 28008555, 27433846, 26681312, 24681528, 28301456, 16953663, 28152038, 25614872, 23807571, 12815592, 15039971, 31871109, 30370249, 21965147, 32832836)
Counsyl RCV000169621 SCV000221148 likely pathogenic Ataxia-telangiectasia syndrome 2015-02-19 criteria provided, single submitter literature only
Invitae RCV000169621 SCV000253746 pathogenic Ataxia-telangiectasia syndrome 2020-10-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp2638*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs377349459, ExAC 0.01%). This variant has been reported in the homozygous or compound heterozygous state in individuals and families affected with ataxia-telangiectasia (PMID: 9711876, 12815592, 15039971, 21965147). It was also observed in an individual with colon cancer and an individual with prostate cancer (PMID: 26681312, 27433846). ClinVar contains an entry for this variant (Variation ID: 141233). 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 RCV000129649 SCV000687802 pathogenic Hereditary cancer-predisposing syndrome 2021-01-04 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 53 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with male breast cancer and prostate, liver, colon cancer and melanoma (PMID: 26681312, 27433846, 28008555), and in homozygous and compound heterozygous carriers affected with ataxia-telangiectasia (PMID: 9711876, 15039971, 21965147). Haplotype analyses suggest this variant may be a founder mutation in individuals of African ancestry (PMID: 12815592, 15039971). This variant has been identified in 5/281730 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169621 SCV000694363 pathogenic Ataxia-telangiectasia syndrome 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The ATM c.7913G>A (p.Trp2638X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM 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.8264_8268delATAAG, p.Tyr2755fsX12; c.8266A>T, p.Lys2756X; c.8287C>T, p.Arg2763X; c.8977C>T, p.Arg2993X). The variant of interest has been found in ExAC in 1/120514 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). This variant was reported in several patients with Ataxia Telangiectasia (A-T) in homozygous state as well as in compound heterozygous state with other pathogenic/ likely pathogenic variants (Sasaki_Hum Mutat_1998, Coutinho_AmJMedGenet_2004, Demuth_Neurogenetics_2011, Nakamura_Mol Genet Genomic Med_2014). Protein expression and ATM-dependent kinase activity assays from patient cells carrying this variant in heterozygous state and compound heterozygous state with another truncating variant are consistent with the predicted outcome (Fernet_BrJC_2004, Nakamura_Mol Genet Genomic Med_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics RCV000169621 SCV000838603 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768151 SCV000898530 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-01-18 criteria provided, single submitter clinical testing ATM NM_000051.3 exon 53 p.Trp2638* (c.7913G>A): This variant has been identified as homozygous or compound heterozygous in at least 6 individuals with ataxia telangiectasia (Sasaki 1998 PMID:9711876, Mitui 2003 PMID:12815592, Coutinho 2004 PMID:15039971, Demuth 2011 PMID:21965147). This variant was also identified in at least 2 individuals with colon or prostate cancer (Pritchard 2016 PMID:27433846, Susswein 2016 PMID:26681312). This variant is present in 4/24010 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs377349459). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:141233). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Huang 2013 PMID:23807571) . In summary, this variant is classified as pathogenic.
Athena Diagnostics Inc RCV000212077 SCV001475571 pathogenic not provided 2020-02-11 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.

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