ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2251-10T>G (rs730881346)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159691 SCV000209697 likely pathogenic not provided 2021-01-11 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: creates a new splice acceptor site, which results in the addition of nine nucleotides and subsequently a truncated protein, but in the absence of RNA studies, we cannot asses the proportion of aberrant transcript (Telatar 1998, Teraoka 1999); Observed as a single heterozygous variant in individuals with breast or pancreatic cancer (Decker 2017, Hu 2018); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek 2016); 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, 10873394, 31447099, 32081490)
Invitae RCV000161929 SCV000211913 pathogenic Ataxia-telangiectasia syndrome 2020-10-01 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. This variant is present in population databases (rs730881346, ExAC 0.002%). This variant has been reported to co-occur with at least 3 different pathogenic ATM variants (c.2806_2809dupCTAG, p.Arg2832Cys, c.8786+1G>A) in individuals with ataxia-telangiectasia (PMID: 9443866, 10330348, 10873394, 9463314, 12552559). While it was not explicitly stated that the two ATM variants in these individuals were on opposite chromosomes, this observation suggests that the c.2251-10T>G substitution contributes to the cause of disease. It has also been observed as homozygous in individuals affected with ataxia-telangiectasia (PMID: 9463314), and as a heterozygous change in an individual with breast cancer (PMID: 26681312). This variant is also known as IVS16-10T>G and 2249ins9nt in the literature. ClinVar contains an entry for this variant (Variation ID: 181926). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant alters RNA splicing by creating a cryptic acceptor splice site 9 nucleotides upstream of the consensus acceptor splice site, leading to the use of a premature stop codon. This prediction is supported by experimental studies, although the data was not made available for review (PMID: 10330348). 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 Health, Inc RCV000580644 SCV000682043 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics 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 2019-04-23 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 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 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). 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 2019-03-22 criteria provided, single submitter clinical testing Variant summary: ATM c.2251-10T>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3 acceptor site. Five predict the variant creates an intronic cryptic 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. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic (2x) and as likely pathogenic (4x). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV001253609 SCV001429425 uncertain significance Familial cancer of breast 2018-10-29 criteria provided, single submitter clinical testing

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