ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.8307G>A (p.Trp2769Ter)

gnomAD frequency: 0.00001  dbSNP: rs778269655
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169516 SCV000220986 likely pathogenic Ataxia-telangiectasia syndrome 2014-12-23 criteria provided, single submitter literature only
Labcorp Genetics (formerly Invitae), Labcorp RCV000169516 SCV000260922 pathogenic Ataxia-telangiectasia syndrome 2024-01-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp2769*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs778269655, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 8845835). ClinVar contains an entry for this variant (Variation ID: 189104). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000579481 SCV000682476 pathogenic Hereditary cancer-predisposing syndrome 2023-03-06 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 57 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 26786923), pancreatic cancer (PMID: 33436325), and in the compound heterozygous state with a second ATM mutation in individuals affected with ataxia-telangiectasia (PMID: 8845835, 22649200). This variant has been identified in 2/251376 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.
Ambry Genetics RCV000579481 SCV001189935 pathogenic Hereditary cancer-predisposing syndrome 2023-10-20 criteria provided, single submitter clinical testing The p.W2769* pathogenic mutation (also known as c.8307G>A), located in coding exon 56 of the ATM gene, results from a G to A substitution at nucleotide position 8307. This changes the amino acid from a tryptophan to a stop codon within coding exon 56. This mutation has been identified in several individuals with Ataxia-telangiectasia (AT) who also carried another mutation in the ATM gene (Gilad S, et al. Hum. Mol. Genet. 1996;5(4):433-9; Jackson TJ et al. Dev. Med. Child Neurol. 2016 07;58:690-7; Ambry internal data). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genetic. 2017 11;54:732-741) and was identified in 2/2000 Australian breast or ovarian cancer patients and 0/1997 controls undergoing multigene panel testing for hereditary cancer risk (Thompson ER et al, J. Clin. Oncol. 2016 May;34:1455-9). 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 RCV001564923 SCV001788165 pathogenic not provided 2023-02-17 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 individuals with a personal or family history of cancers consistent with pathogenic variants in this gene, including breast and prostate cancer (Thompson et al., 2016; Decker et al., 2017; Ghazani et al., 2017; Na et al., 2017; AlDubayan et al., 2018; Li et al., 2019; Karlsson et all., 2021); Observed in the compound heterozygous state in individuals with ataxia-telangiectasia (Gilad et al., 1996; Corts et al., 2003; Rbe et al., 2010); Published functional studies demonstrate a damaging effect: absence of protein expression, loss of kinase activity, and increased sensitivity to ionizing radiation (Corts et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 29752822, 35047863, 8845835, 26786923, 12883528, 29555025, 25133958, 20153123, 29478780, 28779002, 28125075, 27989354, 28716242, 25525159, 33436325, 9259193, 22649200, 29922827, 32338768, 33804961, 32853339, 26896183)
AiLife Diagnostics, AiLife Diagnostics RCV001564923 SCV002501611 pathogenic not provided 2021-12-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169516 SCV002598754 pathogenic Ataxia-telangiectasia syndrome 2022-09-12 criteria provided, single submitter clinical testing Variant summary: ATM c.8307G>A (p.Trp2769X) 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. The variant allele was found at a frequency of 8e-06 in 251376 control chromosomes (gnomAD). c.8307G>A has been reported in the literature in individuals affected with breast cancer or prostate cancer (Decker_2017, Nguyen-Dumont_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003468846 SCV004211990 pathogenic Familial cancer of breast 2023-05-06 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003468846 SCV004931113 pathogenic Familial cancer of breast 2024-02-01 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Natera, Inc. RCV000169516 SCV002079427 pathogenic Ataxia-telangiectasia syndrome 2020-07-23 no assertion criteria provided clinical testing

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