ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.3078G>T (p.Trp1026Cys)

dbSNP: rs876660869
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219464 SCV000278646 pathogenic Hereditary cancer-predisposing syndrome 2022-03-25 criteria provided, single submitter clinical testing The c.3078G>T pathogenic mutation (also known as p.W1026C) is located in coding exon 20 of the ATM gene. The tryptophan at codon 1026 is replaced by cysteine, an amino acid with highly dissimilar properties. This change occurs in the first base pair of coding exon 20. This alteration has been reported in conjunction with other ATM alterations in individuals affected with ataxia-telangiectasia (Chen Z et al. Neurobiol Aging, 2013 Oct;34:2442.e11-7; van Os NJH et al. Clin Immunol, 2017 05;178:45-55; van Os NJH et al. J Neurol, 2020 Mar;267:830-837). This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358).This alteration was also reported in 5/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV000704906 SCV000833879 likely pathogenic Ataxia-telangiectasia syndrome 2023-12-08 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1026 of the ATM protein (p.Trp1026Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 23726790, 28126470). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 234132). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001268471 SCV001447425 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Baylor Genetics RCV003469101 SCV004210195 likely pathogenic Familial cancer of breast 2023-11-22 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003469101 SCV004933474 likely pathogenic Familial cancer of breast 2024-01-18 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23726790, 28126470].
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV004760450 SCV005373767 pathogenic Hereditary breast ovarian cancer syndrome 2024-10-08 criteria provided, single submitter curation According to the ClinGen ACMG ATM v1.3.0 criteria we chose these criteria: PVS1 (very strong pathogenic): Eigene RNA-Analysen (37640): Skipping von Exon 21, . frame shift, monoallelische Expression, r.3078_3153del, p.(His1027Leufs*12), PM2 (supporting pathogenic): Grpmax Filtering AF = 6.215e-7, PM3 (strong pathogenic): Chen (2013, PMID: 23726790): phenotype confident but phase unknown --> 2 P van Os (2017 & 2020, PMID: 28126470 & 31776720): phenotype confident but phase unknown --> 2 P

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