ClinVar Miner

Submissions for variant NM_001351834.2(ATM):c.5763-1050A>G (rs774925473)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229886 SCV000282999 pathogenic Ataxia-telangiectasia syndrome 2020-10-28 criteria provided, single submitter clinical testing This sequence change falls in intron 38 of the ATM mRNA. It does not directly change the encoded amino acid sequence of the ATM protein. This variant is not present in population databases (rs774925473, ExAC no frequency). This variant has been reported in several individuals affected with atypical ataxia-telangiectasia (characterized by later disease onset and/or slower disease progression and attenuated disease features than classical ataxia-telangiectasia) (PMID: 8755918, 21792198, 10330348, 8808599). Notably, one individual carried this variant in trans with a second pathogenic variant, c.9139C>T (p.Arg3047*), and two affected brothers have been reported to be homozygous for this variant (PMID: 10234507, 15174027). This variant is also known as 5762ins137, the 4-1-8 variant, IVS40-1050A>G, IVS40+1126A>G, IVS40ins137, and 5763ins130 in the literature. ClinVar contains an entry for this variant (Variation ID: 3021). Experimental studies have shown that this intronic change results in the insertion of part of intron 38 in between exons 38 and 39, resulting in a frameshift (PMID: 8755918, 19823873). However, this variant is described as a leaky splice site mutation, as only a portion of the transcripts from this allele contain this insertion, as shown by cDNA sequencing (PMID: 8755918). The remaining transcripts expressed from this allele result in low-level expression of ATM protein with near wild-type levels of kinase activity (PMID: 11382771, 25040471). These results may explain the atypical disease associated with this variant. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000229886 SCV000485197 pathogenic Ataxia-telangiectasia syndrome 2016-01-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000494077 SCV000581456 pathogenic Hereditary cancer-predisposing syndrome 2019-06-20 criteria provided, single submitter clinical testing The c.5763-1050A>G intronic pathogenic mutation results from an A to G substitution 1050 nucleotides before coding exon 38 in the ATM gene. This mutation is known to activate a cryptic splice donor site that results in the insertion of 137 nucleotides between coding exon 37 and coding exon 38, leading to a premature stop codon that is expected to trigger nonsense-mediated mRNA decay (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Stewart GS et al. J. Biol. Chem. 2001 Aug 10;276:30133-41). RNA studies have demonstrated that this alteration results in the same splicing event reported in the literature (Ambry internal data). Published studies have also shown that a normal mRNA transcript is produced from the affected allele, albeit at significantly reduced levels (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Sutton IJ et al. Ann. Neurol. 2004 Jun;55:891-5). This mutation has been observed in multiple ataxia telangiectasia (AT) cohorts in both the homozygous and compound heterozygous state, and due to the preservation of some normal ATM protein expression, AT individuals with at least one copy of this mutation show a relatively less severe phenotype than individuals with classic AT (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Sutton IJ et al. Ann. Neurol. 2004 Jun;55:891-5; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 02;161(3):575-586). One study showed that two siblings who were homozygous for this mutation and had exceptionally mild AT phenotypes still had approximately 11% of the level of ATM protein expected in normal cells (Sutton IJ et al. Ann. Neurol. 2004 Jun;55:891-5). This mutation is considered a founder mutation originating in the British Isles, and is seen in the heterozygous state in approximately 15% of AT patients from the UK (Stewart GS et al. J. Biol. Chem. 2001 Aug 10;276:30133-41). Of note, this alteration is also designated as 5762ins137, IVS40-1050A>G, and IVS40+1126A>G in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724150 SCV000700719 pathogenic not provided 2016-12-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000494077 SCV000902857 likely pathogenic Hereditary cancer-predisposing syndrome 2021-02-02 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the -1050 position of intron 38 of the ATM gene. This variant is also known as IVS40-1050A>G and 5762ins137 in the literature. RNA and protein studies have found that this variant causes a partial splicing defect resulting in reduced ATM protein level (PMID: 8755819, 10234507, 15174027, 25040471). Functional studies reported that residual kinase activities were still detectable, indicating a partial loss-of-function (PMID: 8755819, 10234507, 15174027, 25040471). This variant has been reported in homozygous and compound heterozygous carriers with mild ataxia-telangiectasia phenotype (PMID: 8755918, 10234507, 10330348, 15174027, 21792198, 28008555) and two individuals affected with breast cancer (PMID: 19781682, 28008555). This variant has been identified in 5/158620 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant has been observed together with pathogenic variants in the BRCA1 and BRCA2 gene in several individuals (Color internal data). Based on the available evidence, this variant is classified as Likely Pathogenic for autosomal recessive ataxia-telangiectasia. Although this variant is associated with mild ataxia-telangiectasia phenotype, the available evidence is insufficient to determine the role of this variant in autosomal dominant breast cancer phenotype conclusively. Medical management should be considered based on the individual’s personal and family history.
GeneDx RCV000724150 SCV001875224 pathogenic not provided 2021-07-30 criteria provided, single submitter clinical testing Non-canonical splice site variant demonstrated toresult in two transcripts, one with a 137 nucleotide insertion which results in a frameshift, as well as some normal transcript (McConville 1996, Teraoka 1999); Published functional studies demonstrate a damaging effect: cells from individuals carrying this variant have been shown to have reduced ATM protein levels and ATM kinase activity compared to wildtype (Izatt 1999, Stewart 2001, Sutton 2004, Reiman 2011, Taylor 2015); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing.; This variant is associated with the following publications: (PMID: 32255556, 32623769, 30549301, 21792198, 8755918, 21459046, 25040471, 19535770, 12082606, 15928302, 17586848, 19823873, 28008555, 23143971, 15174027, 10330348, 10234507, 9463314, 20301790, 11382771)
OMIM RCV000003157 SCV000023315 pathogenic Ataxia-telangiectasia variant 2004-06-01 no assertion criteria provided literature only
GeneReviews RCV000229886 SCV000328266 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Natera, Inc. RCV000229886 SCV001452329 pathogenic Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.