ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.1607+1G>T

gnomAD frequency: 0.00001  dbSNP: rs772926890
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen RCV002221512 SCV002499296 pathogenic Familial cancer of breast 2022-03-16 reviewed by expert panel curation The ATM c.1607+1G>T canonical splice variant is predicted to result in a truncated protein that disrupts a critical functional domain (PVS1_Strong). This variant has been observed in a homozygous and compound heterozygous state in multiple individuals with Ataxia-Telangiectasia (PMIDs: 10330348, 1712434, 9450906, 19691550, PM3_VeryStrong). This variant has a GnomAD (v2.1.1) allele frequency of 0.0009% (NFE) which is below the ATM PM2 threshold of 0.001% (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel.
Labcorp Genetics (formerly Invitae), Labcorp RCV000203930 SCV000261188 pathogenic Ataxia-telangiectasia syndrome 2023-12-06 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 10 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with ataxia telangiectasia (PMID: 10330348, 17124347). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS12+1G>T. ClinVar contains an entry for this variant (Variation ID: 220555). Studies have shown that disruption of this splice site alters ATM gene expression (PMID: 10330348). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 9443866, 9450906; Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000235749 SCV000293070 pathogenic not provided 2019-07-05 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9443866, 17124347, 9450906, 19691550, 23454770, 25525159, 10330348)
Counsyl RCV000203930 SCV000485314 likely pathogenic Ataxia-telangiectasia syndrome 2015-11-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563715 SCV000667940 pathogenic Hereditary cancer-predisposing syndrome 2023-11-20 criteria provided, single submitter clinical testing The c.1607+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 9 of the ATM gene. This alteration has been detected in multiple homozygous and compound heterozygous individuals of Italian descent with ataxia telangiectasia (A-T) (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun; 64(6):1617-31; Magliozzi M et al. Dis. Markers 2006; 22(4):257-64; Telatar M et al. Am. J. Hum. Genet. 1998 Jan; 62(1):86-97; Chessa L et al. Ann. Hum. Genet. 2009 Sep; 73(Pt 5):532-9; Gilad S et al. Hum. Mutat. 1998;11(1):69-75). Furthermore, functional mRNA studies have shown that this alteration leads to aberrant splicing (Gilad S et al. Hum. Mutat. 1998; 11(1):69-75; Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun; 64(6):1617-31). Further, cells from an individual homozygous for this alteration have been shown to exhibit marked hypersensitivity to DNA damaging agents (i.e. x-rays and potassium bromate), demonstrated by increased chromosomal damage in exposed cells (Mosesso P et al. Mutat Res Genet Toxicol Environ Mutagen. 2018 Dec;836:117-123). Of note, this alteration is also designated as IVS12+1G>T in the published literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health RCV000563715 SCV001351463 pathogenic Hereditary cancer-predisposing syndrome 2023-10-03 criteria provided, single submitter clinical testing This variant causes a G to T nucleotide substitution at the +1 position of intron 10 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have reported that this variant (also known as IVS12+1G>T in the literature) leads to the activation of a cryptic splice site 201 basepair upstream (PMID: 9450906) or the retention of intron 10 (PMID: 10330348). Both mutant transcripts are expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with ataxia telangiectasia (PMID: 9443866, 9450906, 10330348, 19691550, 23454770). This variant has been identified in 2/250010 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 RCV000203930 SCV003929056 pathogenic Ataxia-telangiectasia syndrome 2023-04-03 criteria provided, single submitter clinical testing Variant summary: ATM c.1607+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. One publication reported that the variant resulted in intron retention in a patient derived lymphoblastoid cell line (LCL), which had the variant in homozygous state (Teraoka_1999). The variant allele was found at a frequency of 8e-06 in 250010 control chromosomes (gnomAD). c.1607+1G>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Ataxia-Telangiectasia (e.g. Teraoka_1999, Chessa_2009, Prodosmo_2013). These data indicate that the variant is likely to be associated with disease. Publications reported the lack of ATM protein on western-blot of cells derived from homozygous patients (Teraoka_1999, Prodosmo_2013). Six submitters, including an expert panel (ClinGen), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=5, including the ClinGen Expert panel) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV002221512 SCV004210072 pathogenic Familial cancer of breast 2023-08-05 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV002221512 SCV004932238 likely pathogenic Familial cancer of breast 2024-01-16 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

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