ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.2251-10T>G

gnomAD frequency: 0.00001  dbSNP: rs730881346
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159691 SCV000209697 pathogenic not provided 2024-08-03 criteria provided, single submitter clinical testing Observed as a single heterozygous variant in individuals with breast, pancreatic, or other cancers (PMID: 28779002, 29922827, 32081490); Functional studies demonstrate abnormal splicing: creation of a new splice acceptor site resulting in the addition of nine nucleotides and subsequent protein truncation (PMID: 9443866, 10330348, External communication with Ambry Genetics); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as ATM IVS16-10T>G; This variant is associated with the following publications: (PMID: 28281021, 29922827, 16014569, 12497634, 10330348, 26681312, 16141195, 9463314, 27304073, 21792198, 28182994, 12673797, 9443866, 28779002, 12552559, 31447099, 35626031, 32081490, 34570182, 34539671, 10873394)
Labcorp Genetics (formerly Invitae), Labcorp RCV000161929 SCV000211913 pathogenic Ataxia-telangiectasia syndrome 2024-01-28 criteria provided, single submitter clinical testing This sequence change falls in intron 14 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs730881346, gnomAD 0.002%). This variant has been observed in individuals with ataxia-telangiectasia and/or breast cancer (PMID: 9443866, 9463314, 10330348, 10873394, 12552559, 26681312). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS16-10T>G or 2249ins9nt. ClinVar contains an entry for this variant (Variation ID: 181926). Studies have shown that this variant alters ATM gene expression (PMID: 9463314, 10873394, 21792198). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000515310 SCV000611162 likely pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-18 criteria provided, single submitter clinical testing
Counsyl RCV000161929 SCV000678106 likely pathogenic Ataxia-telangiectasia syndrome 2017-02-09 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000580644 SCV000682043 likely pathogenic Hereditary cancer-predisposing syndrome 2023-10-17 criteria provided, single submitter clinical testing This variant causes a T to G nucleotide substitution at the -10 position of intron 14 of the ATM gene. Splice site prediction tools predict that this variant may create an alternative splice acceptor site. The use of this splice site is predicted to create a premature translation termination signal and is expected to result in an absent or non-functional protein product. Cell lines that are homozygous for this variant are reported to have undetectable ATM protein and autophosphorylation activity (PMID: 28182994). This variant (also known as IVS16-10T>G in the literature) has been reported in the homozygous state and compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 9443866, 9463314, 10330348, 10873394, 12552559, 21792198, 34539671). Cells derived from some of these individuals have shown reduced or absent ATM protein levels and undetectable ATM kinase activity (PMID: 10873394, 21792198). This variant has also been reported in individuals affected with breast cancer and pancreatic cancer (PMID: 26681312, 28281021, 28779002, 29922827). This variant has been identified in 3/281524 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 Likely Pathogenic.
PreventionGenetics, part of Exact Sciences RCV000159691 SCV000805513 pathogenic not provided 2016-01-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000161929 SCV001158080 pathogenic Ataxia-telangiectasia syndrome 2018-12-27 criteria provided, single submitter clinical testing The ATM c.2251-10T>G variant (rs730881346), also known as IVS16-10T>G, is reported in the literature in multiple individuals with ataxia-telangiectasia, both in the homozygous state and in trans to other pathogenic variants (Becker-Catania 2000, Buzin 2003, Stankovic 1998, Telatar 1998). This variant has also been reported in an individual affected with breast cancer (Susswein 2016). The c.2251-10T>G variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 181926), and it is found on only three chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant impacts splicing by creating a novel cryptic acceptor splice site, leading to inclusion of nine nucleotides containing a premature stop codon. RNA studies from patient cells containing this variant support this effect on splicing (Teraoka 1999), and immunoblotting performed on cells homozygous for this variant indicate no detectable ATM variant present (Stankovic 1998, Wang 2017). Based on available information, this variant is considered to be pathogenic. References: Becker-Catania SG et al. Ataxia-telangiectasia: phenotype/genotype studies of ATM protein expression, mutations, and radiosensitivity. Mol Genet Metab. 2000 Jun;70(2):122-33. Buzin CH et al. Comprehensive scanning of the ATM gene with DOVAM-S. Hum Mutat. 2003 Feb;21(2):123-31. Stankovic T et al. ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet. 1998 Feb;62(2):334-45. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. Telatar M et al. Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet. 1998 Jan;62(1):86-97. Teraoka SN et al. Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences. Am J Hum Genet. 1999 Jun;64(6):1617-31. Wang C et al. ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib. Transl Oncol. 2017 Apr;10(2):190-196.
Ambry Genetics RCV000580644 SCV001175711 pathogenic Hereditary cancer-predisposing syndrome 2022-05-12 criteria provided, single submitter clinical testing The c.2251-10T>G intronic pathogenic mutation results from a T to G substitution 10 nucleotides upstream from coding exon 14 in the ATM gene. This alteration has been reported in conjunction with a second, pathogenic mutation in multiple individuals diagnosed with ataxia-telangiectasia (Telatar M et al. Am. J. Hum. Genet. 1998 Jan;62:86-97; Teraoka SN et al. Am. J. Hum. Genet. 1999 June;64:1617-31; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Campbell C et al. Hum. Mutat. 2003 Jan;21:80-85; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31). In addition, this alteration has been identified in individuals diagnosed with breast cancer (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies showed abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000161929 SCV001362540 pathogenic Ataxia-telangiectasia syndrome 2023-12-18 criteria provided, single submitter clinical testing Variant summary: ATM c.2251-10T>G alters a conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 3' acceptor site. Two predict the variant abolishes a 3' acceptor site. Experimental evidence in support of these predictions demonstrated the variant to create a novel splice site and cause the insertion of 9 nucleotides eventually leading to truncation of the protein (Teraoka_1999). The variant allele was found at a frequency of 1.1e-05 in 275962 control chromosomes (gnomAD). c.2251-10T>G has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Reiman_2011, Buzin_2003, Becker-Catania_2000, Telatar_1998). The variant has also been reported in individuals affected with breast and pancreatic cancer (Hu_2018, Susswein_2016). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12552559, 10330348, 10873394, 26681312, 21792198, 9443866, 28281021, 29922827, 28182994). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as pathogenic/likely pathogenic (n=9) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4 RCV000580644 SCV002536447 pathogenic Hereditary cancer-predisposing syndrome 2021-04-22 criteria provided, single submitter curation
Baylor Genetics RCV001253609 SCV004206925 pathogenic Familial cancer of breast 2024-02-09 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV001253609 SCV004933361 likely pathogenic Familial cancer of breast 2024-01-17 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: 9443866, 9463314, 10330348, 10873394, 12552559].
Institute of Human Genetics, University of Leipzig Medical Center RCV001253609 SCV001429425 uncertain significance Familial cancer of breast 2018-10-29 flagged submission clinical testing

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